2024

Jump to: 2023, 2022, 2021

18 pages, 3280 KiB

Open AccessArticle

Leucine Supplementation Prevents the Development of Skeletal Muscle Dysfunction in a Rat Model of HFpEF

by Paula Ketilly Nascimento Alves, Antje Schauer, Antje Augstein, Maria-Elisa Prieto Jarabo, Anita Männel, Peggy Barthel, Beatrice Vahle, Anselmo S. Moriscot, Axel Linke and Volker Adams

Cells 2024, 13(6), 502; https://doi.org/10.3390/cells13060502 - 13 Mar 2024

Viewed by 761

Abstract

Heart failure with preserved ejection fraction (HFpEF) is associated with exercise intolerance due to alterations in the skeletal muscle (SKM). Leucine supplementation is known to alter the anabolic/catabolic balance and to improve mitochondrial function. Thus, we investigated the effect of leucine supplementation in [...] Read more.

Heart failure with preserved ejection fraction (HFpEF) is associated with exercise intolerance due to alterations in the skeletal muscle (SKM). Leucine supplementation is known to alter the anabolic/catabolic balance and to improve mitochondrial function. Thus, we investigated the effect of leucine supplementation in both a primary and a secondary prevention approach on SKM function and factors modulating muscle function in an established HFpEF rat model. Female ZSF1 obese rats were randomized to an untreated, a primary prevention, and a secondary prevention group. For primary prevention, leucine supplementation was started before the onset of HFpEF (8 weeks of age) and for secondary prevention, leucine supplementation was started after the onset of HFpEF (20 weeks of age). SKM function was assessed at an age of 32 weeks, and SKM tissue was collected for the assessment of mitochondrial function and histological and molecular analyses. Leucine supplementation prevented the development of SKM dysfunction whereas it could not reverse it. In the primary prevention group, mitochondrial function improved and higher expressions of mitofilin, Mfn-2, Fis1, and miCK were evident in SKM. The expression of UCP3 was reduced whereas the mitochondrial content and markers for catabolism (MuRF1, MAFBx), muscle cross-sectional area, and SKM mass did not change. Our data show that leucine supplementation prevented the development of skeletal muscle dysfunction in a rat model of HFpEF, which may be mediated by improving mitochondrial function through modulating energy transfer. Full article

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15 pages, 4451 KiB

Open AccessArticle

Isolevuglandins Promote Mitochondrial Dysfunction and Electrophysiologic Abnormalities in Atrial Cardiomyocytes

by Tuerdi Subati, Zhenjiang Yang, Matthew B. Murphy, Joshua M. Stark, David Z. Trykall, Sean S. Davies, Joey V. Barnett and Katherine T. Murray

Cells 2024, 13(6), 483; https://doi.org/10.3390/cells13060483 - 09 Mar 2024

Viewed by 857

Abstract

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, yet the cellular and molecular mechanisms underlying the AF substrate remain unclear. Isolevuglandins (IsoLGs) are highly reactive lipid dicarbonyl products that mediate oxidative stress-related injury. In murine hypertension, the lipid dicarbonyl scavenger 2-hydroxybenzylamine [...] Read more.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, yet the cellular and molecular mechanisms underlying the AF substrate remain unclear. Isolevuglandins (IsoLGs) are highly reactive lipid dicarbonyl products that mediate oxidative stress-related injury. In murine hypertension, the lipid dicarbonyl scavenger 2-hydroxybenzylamine (2-HOBA) reduced IsoLGs and AF susceptibility. We hypothesized that IsoLGs mediate detrimental pathophysiologic effects in atrial cardiomyocytes that promote the AF substrate. Using Seahorse XFp extracellular flux analysis and a luminescence assay, IsoLG exposure suppressed intracellular ATP production in atrial HL-1 cardiomyocytes. IsoLGs caused mitochondrial dysfunction, with reduced mitochondrial membrane potential, increased mitochondrial reactive oxygen species (ROS) with protein carbonylation, and mitochondrial DNA damage. Moreover, they generated cytosolic preamyloid oligomers previously shown to cause similar detrimental effects in atrial cells. In mouse atrial and HL-1 cells, patch clamp experiments demonstrated that IsoLGs rapidly altered action potentials (AP), implying a direct effect independent of oligomer formation by reducing the maximum Phase 0 upstroke slope and shortening AP duration due to ionic current modifications. IsoLG-mediated mitochondrial and electrophysiologic abnormalities were blunted or totally prevented by 2-HOBA. These findings identify IsoLGs as novel mediators of oxidative stress-dependent atrial pathophysiology and support the investigation of dicarbonyl scavengers as a novel therapeutic approach to prevent AF. Full article

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2023

Jump to: 2024, 2022, 2021

28 pages, 10412 KiB

Open AccessArticle

Understanding Bartonella-Associated Infective Endocarditis: Examining Heart Valve and Vegetation Appearance and the Role of Neutrophilic Leukocytes

by Kristians Meidrops, Valerija Groma, Niks Ricards Goldins, Lauma Apine, Sandra Skuja, Simons Svirskis, Dita Gudra, Davids Fridmanis and Peteris Stradins

Cells 2024, 13(1), 43; https://doi.org/10.3390/cells13010043 - 25 Dec 2023

Viewed by 1107

Abstract

Background. The endocardium and cardiac valves undergo severe impact during infective endocarditis (IE), and the formation of vegetation places IE patients at a heightened risk of embolic complications and mortality. The relevant literature indicates that 50% of IE cases exhibit structurally normal cardiac [...] Read more.

Background. The endocardium and cardiac valves undergo severe impact during infective endocarditis (IE), and the formation of vegetation places IE patients at a heightened risk of embolic complications and mortality. The relevant literature indicates that 50% of IE cases exhibit structurally normal cardiac valves, with no preceding history of heart valve disease. Gram-positive cocci emerge as the predominant causative microorganisms in IE, while Gram-negative Bartonella spp., persisting in the endothelium, follow pathogenic pathways distinct from those of typical IE-causing agents. Employing clinical as well as advanced microbiological and molecular assays facilitated the identification of causative pathogens, and various morphological methods were applied to evaluate heart valve damage, shedding light on the role of neutrophilic leukocytes in host defense. In this research, the immunohistochemical analysis of neutrophilic leukocyte activation markers such as myeloperoxidase, neutrophil elastase, calprotectin, and histone H3, was performed. A distinct difference in the expression patterns of these markers was observed when comparing Bartonella spp.-caused and non-Bartonella spp.-caused IE. The markers exhibited significantly higher expression in non-Bartonella spp.-caused IE compared to Bartonella spp.-caused IE, and they were more prevalent in vegetation than in the valvular leaflets. Notably, the expression of these markers in all IE cases significantly differed from that in control samples. Furthermore, we advocated the use of 16S rRNA Next-Generation Sequencing on excised heart valves as an effective diagnostic tool for IE, particularly in cases where blood cultures yielded negative results. The compelling results achieved in this study regarding the enigmatic nature of Bartonella spp. IE’s pathophysiology contribute significantly to our understanding of the peculiarities of inflammation and immune responses. Full article

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19 pages, 2620 KiB

Open AccessArticle

Cholesteryl Hemiazelate Present in Cardiovascular Disease Patients Causes Lysosome Dysfunction in Murine Fibroblasts

by Elizeth Lopes, Gisela Machado-Oliveira, Catarina Guerreiro Simões, Inês S. Ferreira, Cristiano Ramos, José Ramalho, Maria I. L. Soares, Teresa M. V. D. Pinho e Melo, Rosa Puertollano, André R. A. Marques and Otília V. Vieira

Cells 2023, 12(24), 2826; https://doi.org/10.3390/cells12242826 - 13 Dec 2023

Viewed by 1028

Abstract

There is growing evidence supporting the role of fibroblasts in all stages of atherosclerosis, from the initial phase to fibrous cap and plaque formation. In the arterial wall, as with macrophages and vascular smooth muscle cells, fibroblasts are exposed to a myriad of [...] Read more.

There is growing evidence supporting the role of fibroblasts in all stages of atherosclerosis, from the initial phase to fibrous cap and plaque formation. In the arterial wall, as with macrophages and vascular smooth muscle cells, fibroblasts are exposed to a myriad of LDL lipids, including the lipid species formed during the oxidation of their polyunsaturated fatty acids of cholesteryl esters (PUFA-CEs). Recently, our group identified the final oxidation products of the PUFA-CEs, cholesteryl hemiesters (ChE), in tissues from cardiovascular disease patients. Cholesteryl hemiazelate (ChA), the most prevalent lipid of this family, is sufficient to impact lysosome function in macrophages and vascular smooth muscle cells, with consequences for their homeostasis. Here, we show that the lysosomal compartment of ChA-treated fibroblasts also becomes dysfunctional. Indeed, fibroblasts exposed to ChA exhibited a perinuclear accumulation of enlarged lysosomes full of neutral lipids. However, this outcome did not trigger de novo lysosome biogenesis, and only the lysosomal transcription factor E3 (TFE3) was slightly transcriptionally upregulated. As a consequence, autophagy was inhibited, probably via mTORC1 activation, culminating in fibroblasts’ apoptosis. Our findings suggest that the impairment of lysosome function and autophagy and the induction of apoptosis in fibroblasts may represent an additional mechanism by which ChA can contribute to the progression of atherosclerosis. Full article

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24 pages, 5065 KiB

Open AccessArticle

Leucine Supplementation Improves Diastolic Function in HFpEF by HDAC4 Inhibition

by Paula Ketilly Nascimento Alves, Antje Schauer, Antje Augstein, Anita Männel, Peggy Barthel, Dirk Joachim, Janet Friedrich, Maria-Elisa Prieto, Anselmo Sigari Moriscot, Axel Linke and Volker Adams

Cells 2023, 12(21), 2561; https://doi.org/10.3390/cells12212561 - 02 Nov 2023

Cited by 1 | Viewed by 1196

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome associated with a high morbidity and mortality rate. Leucine supplementation has been demonstrated to attenuate cardiac dysfunction in animal models of cachexia and heart failure with reduced ejection fraction (HFrEF). So far, [...] Read more.

Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome associated with a high morbidity and mortality rate. Leucine supplementation has been demonstrated to attenuate cardiac dysfunction in animal models of cachexia and heart failure with reduced ejection fraction (HFrEF). So far, no data exist on leucine supplementation on cardiac function in HFpEF. Thus, the current study aimed to investigate the effect of leucine supplementation on myocardial function and key signaling pathways in an established HFpEF rat model. Female ZSF1 rats were randomized into three groups: Control (untreated lean rats), HFpEF (untreated obese rats), and HFpEF_Leu (obese rats receiving standard chow enriched with 3% leucine). Leucine supplementation started at 20 weeks of age after an established HFpEF was confirmed in obese rats. In all animals, cardiac function was assessed by echocardiography at baseline and throughout the experiment. At the age of 32 weeks, hemodynamics were measured invasively, and myocardial tissue was collected for assessment of mitochondrial function and for histological and molecular analyses. Leucine had already improved diastolic function after 4 weeks of treatment. This was accompanied by improved hemodynamics and reduced stiffness, as well as by reduced left ventricular fibrosis and hypertrophy. Cardiac mitochondrial respiratory function was improved by leucine without alteration of the cardiac mitochondrial content. Lastly, leucine supplementation suppressed the expression and nuclear localization of HDAC4 and was associated with Protein kinase A activation. Our data show that leucine supplementation improves diastolic function and decreases remodeling processes in a rat model of HFpEF. Beneficial effects were associated with HDAC4/TGF-β1/Collagenase downregulation and indicate a potential use in the treatment of HFpEF. Full article

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19 pages, 4402 KiB

Open AccessArticle

Transgenic Mice Expressing Functional TCRs Specific to Cardiac Myhc-α 334–352 on Both CD4 and CD8 T Cells Are Resistant to the Development of Myocarditis on C57BL/6 Genetic Background

by Meghna Sur, Mahima T. Rasquinha, Rajkumar Arumugam, Chandirasegaran Massilamany, Arunkumar Gangaplara, Kiruthiga Mone, Ninaad Lasrado, Bharathi Yalaka, Aakash Doiphode, Channabasavaiah Gurumurthy, David Steffen and Jay Reddy

Cells 2023, 12(19), 2346; https://doi.org/10.3390/cells12192346 - 25 Sep 2023

Cited by 1 | Viewed by 2248

Abstract

Myocarditis is a predominant cause of congestive heart failure and sudden death in children and young adolescents that can lead to dilated cardiomyopathy. Lymphocytic myocarditis mediated by T cells can result from the recognition of cardiac antigens that may involve CD4 or CD8 [...] Read more.

Myocarditis is a predominant cause of congestive heart failure and sudden death in children and young adolescents that can lead to dilated cardiomyopathy. Lymphocytic myocarditis mediated by T cells can result from the recognition of cardiac antigens that may involve CD4 or CD8 T cells or both. In this report, we describe the generation of T cell receptor (TCR) transgenic mice on a C57BL/6 genetic background specific to cardiac myosin heavy chain (Myhc)-α 334–352 and make the following observations: First, we verified that Myhc-α 334–352 was immunogenic in wild-type C57BL/6 mice and induced antigen-specific CD4 T cell responses despite being a poor binder of IA^b; however, the immunized animals developed only mild myocarditis. Second, TCRs specific to Myhc-α 334–352 in transgenic mice were expressed in both CD4 and CD8 T cells, suggesting that the expression of epitope-specific TCR is common to both cell types. Third, although T cells from naïve transgenic mice did not respond to Myhc-α 334–352, both CD4 and CD8 T cells from animals immunized with Myhc-α 334–352 responded to the peptide, indicating that antigen priming is necessary to break tolerance. Fourth, although the transgenic T cells could produce significant amounts of interferon-γ and interleukin-17, the immunized animals developed only mild disease, indicating that other soluble factors might be necessary for developing severe myocarditis. Alternatively, the C57BL/6 genetic background might be a major contributing factor for resistance to the development of myocarditis. Taken together, our model permits the determination of the roles of both CD4 and CD8 T cells to understand the disease-resistance mechanisms of myocarditis in a single transgenic system antigen-specifically. Full article

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28 pages, 8040 KiB

Open AccessArticle

Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk

by Aurora Gómez-Vecino, Roberto Corchado-Cobos, Adrián Blanco-Gómez, Natalia García-Sancha, Sonia Castillo-Lluva, Ana Martín-García, Marina Mendiburu-Eliçabe, Carlos Prieto, Sara Ruiz-Pinto, Guillermo Pita, Alejandro Velasco-Ruiz, Carmen Patino-Alonso, Purificación Galindo-Villardón, María Linarejos Vera-Pedrosa, José Jalife, Jian-Hua Mao, Guillermo Macías de Plasencia, Andrés Castellanos-Martín, María del Mar Sáez-Freire, Susana Fraile-Martín, Telmo Rodrigues-Teixeira, Carmen García-Macías, Julie Milena Galvis-Jiménez, Asunción García-Sánchez, María Isidoro-García, Manuel Fuentes, María Begoña García-Cenador, Francisco Javier García-Criado, Juan Luis García-Hernández, María Ángeles Hernández-García, Juan Jesús Cruz-Hernández, César Augusto Rodríguez-Sánchez, Alejandro Martín García-Sancho, Estefanía Pérez-López, Antonio Pérez-Martínez, Federico Gutiérrez-Larraya, Antonio J. Cartón, José Ángel García-Sáenz, Ana Patiño-García, Miguel Martín, Teresa Alonso-Gordoa, Christof Vulsteke, Lieselot Croes, Sigrid Hatse, Thomas Van Brussel, Diether Lambrechts, Hans Wildiers, Hang Chang, Marina Holgado-Madruga, Anna González-Neira, Pedro L. Sánchez and Jesús Pérez Losada Show full author list Hide full author list

Cells 2023, 12(15), 1956; https://doi.org/10.3390/cells12151956 - 27 Jul 2023

Viewed by 1859

Abstract

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium [...] Read more.

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management. Full article

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26 pages, 2289 KiB

Open AccessReview

A Review of Progress on Targeting LDL Receptor-Dependent and -Independent Pathways for the Treatment of Hypercholesterolemia, a Major Risk Factor of ASCVD

by Rai Ajit K. Srivastava

Cells 2023, 12(12), 1648; https://doi.org/10.3390/cells12121648 - 16 Jun 2023

Cited by 5 | Viewed by 2976

Abstract

Since the discovery of the LDL receptor in 1973 by Brown and Goldstein as a causative protein in hypercholesterolemia, tremendous amounts of effort have gone into finding ways to manage high LDL cholesterol in familial hypercholesterolemic (HoFH and HeFH) individuals with loss-of-function mutations [...] Read more.

Since the discovery of the LDL receptor in 1973 by Brown and Goldstein as a causative protein in hypercholesterolemia, tremendous amounts of effort have gone into finding ways to manage high LDL cholesterol in familial hypercholesterolemic (HoFH and HeFH) individuals with loss-of-function mutations in the LDL receptor (LDLR) gene. Statins proved to be the first blockbuster drug, helping both HoFH and HeFH individuals by inhibiting the cholesterol synthesis pathway rate-limiting enzyme HMG-CoA reductase and inducing the LDL receptor. However, statins could not achieve the therapeutic goal of LDL. Other therapies targeting LDLR include PCSK9, which lowers LDLR by promoting LDLR degradation. Inducible degrader of LDLR (IDOL) also controls the LDLR protein, but an IDOL-based therapy is yet to be developed. Among the LDLR-independent pathways, such as angiopoietin-like 3 (ANGPTL3), apolipoprotein (apo) B, apoC-III and CETP, only ANGPTL3 offers the advantage of treating both HoFH and HeFH patients and showing relatively better preclinical and clinical efficacy in animal models and hypercholesterolemic individuals, respectively. While loss-of-LDLR-function mutations have been known for decades, gain-of-LDLR-function mutations have recently been identified in some individuals. The new information on gain of LDLR function, together with CRISPR-Cas9 genome/base editing technology to target LDLR and ANGPTL3, offers promise to HoFH and HeFH individuals who are at a higher risk of developing atherosclerotic cardiovascular disease (ASCVD). Full article

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13 pages, 2548 KiB

Open AccessCommunication

PAI-1 Overexpression in Valvular Interstitial Cells Contributes to Hypofibrinolysis in Aortic Stenosis

by Magdalena Kopytek, Michał Ząbczyk, Piotr Mazur, Anetta Undas and Joanna Natorska

Cells 2023, 12(10), 1402; https://doi.org/10.3390/cells12101402 - 16 May 2023

Cited by 2 | Viewed by 1434

Abstract

Aortic stenosis (AS) is associated with hypofibrinolysis, but its mechanism is poorly understood. We investigated whether LDL cholesterol affects plasminogen activator inhibitor 1 (PAI-1) expression, which may contribute to hypofibrinolysis in AS. Stenotic valves were obtained from 75 severe AS patients during valve [...] Read more.

Aortic stenosis (AS) is associated with hypofibrinolysis, but its mechanism is poorly understood. We investigated whether LDL cholesterol affects plasminogen activator inhibitor 1 (PAI-1) expression, which may contribute to hypofibrinolysis in AS. Stenotic valves were obtained from 75 severe AS patients during valve replacement to assess lipids accumulation, together with PAI-1 and nuclear factor-κB (NF-κB) expression. Five control valves from autopsy healthy individuals served as controls. The expression of PAI-1 in valve interstitial cells (VICs) after LDL stimulation was assessed at protein and mRNA levels. PAI-1 activity inhibitor (TM5275) and NF-κB inhibitor (BAY 11-7082) were used to suppress PAI-1 activity or NF-κB pathway. Clot lysis time (CLT) was performed to assess fibrinolytic capacity in VICs cultures. Solely AS valves showed PAI-1 expression, the amount of which was correlated with lipid accumulation and AS severity and co-expressed with NF-κB. In vitro VICs showed abundant PAI-1 expression. LDL stimulation increased PAI-1 levels in VICs supernatants and prolonged CLT. PAI-1 activity inhibition shortened CLT, while NF-κB inhibition decreased PAI-1 and SERPINE1 expression in VICs, its level in supernatants and shortened CLT. In severe AS, valvular PAI-1 overexpression driven by lipids accumulation contributes to hypofibrinolysis and AS severity. Full article

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14 pages, 1050 KiB

Open AccessReview

Preclinical Large Animal Porcine Models for Cardiac Regeneration and Its Clinical Translation: Role of hiPSC-Derived Cardiomyocytes

by Divya Sridharan, Nooruddin Pracha, Schaza Javed Rana, Salmman Ahmed, Anam J. Dewani, Syed Baseeruddin Alvi, Muhamad Mergaye, Uzair Ahmed and Mahmood Khan

Cells 2023, 12(7), 1090; https://doi.org/10.3390/cells12071090 - 05 Apr 2023

Cited by 3 | Viewed by 2156

Abstract

Myocardial Infarction (MI) occurs due to a blockage in the coronary artery resulting in ischemia and necrosis of cardiomyocytes in the left ventricular heart muscle. The dying cardiac tissue is replaced with fibrous scar tissue, causing a decrease in myocardial contractility and thus [...] Read more.

Myocardial Infarction (MI) occurs due to a blockage in the coronary artery resulting in ischemia and necrosis of cardiomyocytes in the left ventricular heart muscle. The dying cardiac tissue is replaced with fibrous scar tissue, causing a decrease in myocardial contractility and thus affecting the functional capacity of the myocardium. Treatments, such as stent placements, cardiac bypasses, or transplants are beneficial but with many limitations, and may decrease the overall life expectancy due to related complications. In recent years, with the advent of human induced pluripotent stem cells (hiPSCs), newer avenues using cell-based approaches for the treatment of MI have emerged as a potential for cardiac regeneration. While hiPSCs and their derived differentiated cells are promising candidates, their translatability for clinical applications has been hindered due to poor preclinical reproducibility. Various preclinical animal models for MI, ranging from mice to non-human primates, have been adopted in cardiovascular research to mimic MI in humans. Therefore, a comprehensive literature review was essential to elucidate the factors affecting the reproducibility and translatability of large animal models. In this review article, we have discussed different animal models available for studying stem-cell transplantation in cardiovascular applications, mainly focusing on the highly translatable porcine MI model. Full article

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17 pages, 50462 KiB

Open AccessFeature PaperArticle

Actin-Cytoskeleton Drives Caveolae Signaling to Mitochondria during Postconditioning

by Francisco Correa, Cristina Enríquez-Cortina, Alejandro Silva-Palacios, Nadia Román-Anguiano, Aurora Gil-Hernández, Marcos Ostolga-Chavarría, Elizabeth Soria-Castro, Sharik Hernández-Rizo, Paola de los Heros, María Chávez-Canales and Cecilia Zazueta

Cells 2023, 12(3), 492; https://doi.org/10.3390/cells12030492 - 02 Feb 2023

Viewed by 2200

Abstract

Caveolae-associated signaling toward mitochondria contributes to the cardioprotective mechanisms against ischemia-reperfusion (I/R) injury induced by ischemic postconditioning. In this work, we evaluated the role that the actin-cytoskeleton network exerts on caveolae-mitochondria communication during postconditioning. Isolated rat hearts subjected to I/R and to postconditioning [...] Read more.

Caveolae-associated signaling toward mitochondria contributes to the cardioprotective mechanisms against ischemia-reperfusion (I/R) injury induced by ischemic postconditioning. In this work, we evaluated the role that the actin-cytoskeleton network exerts on caveolae-mitochondria communication during postconditioning. Isolated rat hearts subjected to I/R and to postconditioning were treated with latrunculin A, a cytoskeleton disruptor. Cardiac function was compared between these hearts and those exposed only to I/R and to the cardioprotective maneuver. Caveolae and mitochondria structures were determined by electron microscopy and maintenance of the actin-cytoskeleton was evaluated by phalloidin staining. Caveolin-3 and other putative caveolae-conforming proteins were detected by immunoblot analysis. Co-expression of caveolin-3 and actin was evaluated both in lipid raft fractions and in heart tissue from the different groups. Mitochondrial function was assessed by respirometry and correlated with cholesterol levels. Treatment with latrunculin A abolishes the cardioprotective postconditioning effect, inducing morphological and structural changes in cardiac tissue, reducing F-actin staining and diminishing caveolae formation. Latrunculin A administration to post-conditioned hearts decreases the interaction between caveolae-forming proteins, the co-localization of caveolin with actin and inhibits oxygen consumption rates in both subsarcolemmal and interfibrillar mitochondria. We conclude that actin-cytoskeleton drives caveolae signaling to mitochondria during postconditioning, supporting their functional integrity and contributing to cardiac adaption against reperfusion injury. Full article

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2022

Jump to: 2024, 2023, 2021

44 pages, 17940 KiB

Open AccessArticle

tRNA-like Transcripts from the NEAT1-MALAT1 Genomic Region Critically Influence Human Innate Immunity and Macrophage Functions

by Martina Gast, Vanasa Nageswaran, Andreas W. Kuss, Ana Tzvetkova, Xiaomin Wang, Liliana H. Mochmann, Pegah Ramezani Rad, Stefan Weiss, Stefan Simm, Tanja Zeller, Henry Voelzke, Wolfgang Hoffmann, Uwe Völker, Stefan B. Felix, Marcus Dörr, Antje Beling, Carsten Skurk, David-Manuel Leistner, Bernhard H. Rauch, Tetsuro Hirose, Bettina Heidecker, Karin Klingel, Shinichi Nakagawa, Wolfram C. Poller, Filip K. Swirski, Arash Haghikia and Wolfgang Poller Show full author list Hide full author list

Cells 2022, 11(24), 3970; https://doi.org/10.3390/cells11243970 - 08 Dec 2022

Cited by 5 | Viewed by 2587

Abstract

The evolutionary conserved NEAT1-MALAT1 gene cluster generates large noncoding transcripts remaining nuclear, while tRNA-like transcripts (mascRNA, menRNA) enzymatically generated from these precursors translocate to the cytosol. Whereas functions have been assigned to the nuclear transcripts, data on biological functions of the small cytosolic [...] Read more.

The evolutionary conserved NEAT1-MALAT1 gene cluster generates large noncoding transcripts remaining nuclear, while tRNA-like transcripts (mascRNA, menRNA) enzymatically generated from these precursors translocate to the cytosol. Whereas functions have been assigned to the nuclear transcripts, data on biological functions of the small cytosolic transcripts are sparse. We previously found NEAT1^−/− and MALAT1^−/− mice to display massive atherosclerosis and vascular inflammation. Here, employing selective targeted disruption of menRNA or mascRNA, we investigate the tRNA-like molecules as critical components of innate immunity. CRISPR-generated human ΔmascRNA and ΔmenRNA monocytes/macrophages display defective innate immune sensing, loss of cytokine control, imbalance of growth/angiogenic factor expression impacting upon angiogenesis, and altered cell–cell interaction systems. Antiviral response, foam cell formation/oxLDL uptake, and M1/M2 polarization are defective in ΔmascRNA/ΔmenRNA macrophages, defining first biological functions of menRNA and describing new functions of mascRNA. menRNA and mascRNA represent novel components of innate immunity arising from the noncoding genome. They appear as prototypes of a new class of noncoding RNAs distinct from others (miRNAs, siRNAs) by biosynthetic pathway and intracellular kinetics. Their NEAT1-MALAT1 region of origin appears as archetype of a functionally highly integrated RNA processing system. Full article

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14 pages, 5136 KiB

Open AccessArticle

Mineralocorticoid Receptor Antagonists Mitigate Mitral Regurgitation-Induced Myocardial Dysfunction

by Wei-Ting Chang, Yu-Wen Lin, Chin-Yu Chen, Zhih-Cherng Chen, Jhih-Yuan Shih, Chia-Ching Wu, Chwan-Yau Luo and Ping-Yen Liu

Cells 2022, 11(17), 2750; https://doi.org/10.3390/cells11172750 - 03 Sep 2022

Viewed by 1609

Abstract

Mitral regurgitation (MR), the disruption of the mitral valve, contributes to heart failure (HF). Under conditions of volume overload, excess mineralocorticoids promote cardiac fibrosis. The mineralocorticoid receptor antagonist spironolactone is a potassium-sparing diuretic and a guideline-recommended therapy for HF, but whether it can [...] Read more.

Mitral regurgitation (MR), the disruption of the mitral valve, contributes to heart failure (HF). Under conditions of volume overload, excess mineralocorticoids promote cardiac fibrosis. The mineralocorticoid receptor antagonist spironolactone is a potassium-sparing diuretic and a guideline-recommended therapy for HF, but whether it can ameliorate degenerative MR remains unknown. Herein, we investigate the efficacy of spironolactone in improving cardiac remodeling in MR-induced HF compared with that of a loop diuretic, furosemide. Using a novel and mini-invasive technique, we established a rat model of MR. We treated the rats with spironolactone or furosemide for twelve weeks. The levels of cardiac fibrosis, apoptosis, and stress-associated proteins were then measured. In parallel, we compared the cardiac remodeling of 165 patients with degenerative MR receiving either spironolactone or furosemide. Echocardiography was performed at baseline and at six months. In MR rats treated with spironolactone, left ventricular function—especially when strained—and the pressure volume relationship significantly improved compared to those of rats treated with furosemide. Spironolactone treatment demonstrated significant attenuation of cardiac fibrosis and apoptosis in left ventricular tissue compared to furosemide. Further, spironolactone suppressed the expression of apoptosis-, NADPH oxidase 4 (NOX4)- and inducible nitric oxide synthase (iNOS)-associated proteins. Similarly, compared with MR patients receiving furosemide those prescribed spironolactone demonstrated a trend toward reduction in MR severity and showed improvement in left ventricular function. Collectively, MR-induced cardiovascular dysfunction, including fibrosis and apoptosis, was effectively attenuated by spironolactone treatment. Our findings suggest a potential therapeutic option for degenerative MR-induced HF. Full article

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14 pages, 488 KiB

Open AccessReview

The Role of Cardiac Resynchronization Therapy for the Management of Functional Mitral Regurgitation

by Eleonora Russo, Giulio Russo, Mauro Cassese, Maurizio Braccio, Massimo Carella, Paolo Compagnucci, Antonio Dello Russo and Michela Casella

Cells 2022, 11(15), 2407; https://doi.org/10.3390/cells11152407 - 04 Aug 2022

Cited by 4 | Viewed by 1981

Abstract

Valve leaflets and chordae structurally normal characterize functional mitral regurgitation (FMR), which in heart failure (HF) setting results from an imbalance between closing and tethering forces secondary to alterations in the left ventricle (LV) and left atrium geometry. In this context, FMR impacts [...] Read more.

Valve leaflets and chordae structurally normal characterize functional mitral regurgitation (FMR), which in heart failure (HF) setting results from an imbalance between closing and tethering forces secondary to alterations in the left ventricle (LV) and left atrium geometry. In this context, FMR impacts the quality of life and increases mortality. Despite multiple medical and surgical attempts to treat FMR, to date, there is no univocal treatment for many patients. The pathophysiology of FMR is highly complex and involves several underlying mechanisms. Left ventricle dyssynchrony may contribute to FMR onset and worsening and represents an important target for FMR management. In this article, we discuss the mechanisms of FMR and review the potential therapeutic role of CRT, providing a comprehensive review of the available data coming from clinical studies and trials. Full article

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17 pages, 1988 KiB

Open AccessArticle

Degree of Fibrosis in Human Atrial Tissue Is Not the Hallmark Driving AF

by Kennedy S. Ramos, Lisa Pool, Mathijs S. van Schie, Leonoor F. J. M. Wijdeveld, Willemijn F. B. van der Does, Luciënne Baks, H. M. Danish Sultan, Stan W. van Wijk, Ad J. J. C. Bogers, Sander Verheule, Natasja M. S. de Groot and Bianca J. J. M. Brundel

Cells 2022, 11(3), 427; https://doi.org/10.3390/cells11030427 - 26 Jan 2022

Cited by 9 | Viewed by 4805

Abstract

Background: The current paradigm is that fibrosis promotes electrophysiological disorders and drives atrial fibrillation (AF). In this current study, we investigated the relation between the degree of fibrosis in human atrial tissue samples of controls and patients in various stages of AF and [...] Read more.

Background: The current paradigm is that fibrosis promotes electrophysiological disorders and drives atrial fibrillation (AF). In this current study, we investigated the relation between the degree of fibrosis in human atrial tissue samples of controls and patients in various stages of AF and the degree of electrophysiological abnormalities. Methods: The degree of fibrosis was measured in the atrial tissue and serum of patients in various stages of AF and the controls. Hereto, picrosirius and H&E staining were performed to quantify degree of total, endo-perimysial fibrosis, and cardiomyocyte diameter. Western blot quantified fibrosis markers: neural cell adhesion molecule, tissue inhibitor of metalloproteinase, lysyl oxidase, and α-smooth muscle actin. In serum, the ratio carboxyl-terminal telopeptide of collagen/matrix-metalloproteinase1 was determined. High-resolution epicardial mapping evaluated low-voltage areas and conduction abnormalities. Results: No significant differences were observed in the degree of fibrosis between the groups. Finally, no significant correlation—absolute nor spatial—was observed between all electrophysiological parameters and histological fibrosis markers. Conclusions: No differences in the degree of fibrosis were observed in patients from various stages of AF compared to the controls. Moreover, electrophysiological abnormalities did not correlate with any of the fibrosis markers. The findings indicate that fibrosis is not the hallmark of structural remodeling in AF. Full article

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22 pages, 7662 KiB

Open AccessEditor’s ChoiceArticle

Single-Cell RNA-Seq Reveals a Crosstalk between Hyaluronan Receptor LYVE-1-Expressing Macrophages and Vascular Smooth Muscle Cells

by Fabienne Burger, Daniela Baptista, Aline Roth, Karim J. Brandt, Rafaela Fernandes da Silva, Fabrizio Montecucco, François Mach and Kapka Miteva

Cells 2022, 11(3), 411; https://doi.org/10.3390/cells11030411 - 25 Jan 2022

Cited by 15 | Viewed by 5136

Abstract

Background: Atherosclerosis is a chronic inflammatory disease where macrophages participate in the progression of the disease. However, the role of resident-like macrophages (res-like) in the atherosclerotic aorta is not completely understood. Methods: A single-cell RNA sequencing analysis of CD45⁺ leukocytes in [...] Read more.

Background: Atherosclerosis is a chronic inflammatory disease where macrophages participate in the progression of the disease. However, the role of resident-like macrophages (res-like) in the atherosclerotic aorta is not completely understood. Methods: A single-cell RNA sequencing analysis of CD45⁺ leukocytes in the atherosclerotic aorta of apolipoprotein E–deficient (Apoe^−/−) mice on a normal cholesterol diet (NCD) or a high cholesterol diet (HCD), respecting the side-to-specific predisposition to atherosclerosis, was performed. A population of res-like macrophages expressing hyaluronan receptor LYVE-1 was investigated via flow cytometry, co-culture experiments, and immunofluorescence in human atherosclerotic plaques from carotid artery disease patients (CAD). Results: We identified 12 principal leukocyte clusters with distinct atherosclerosis disease-relevant gene expression signatures. LYVE-1⁺ res-like macrophages, expressing a high level of CC motif chemokine ligand 24 (CCL24, eotaxin-2), expanded under hypercholesteremia in Apoe^−/− mice and promoted VSMC phenotypic modulation to osteoblast/chondrocyte-like cells, ex vivo, in a CCL24-dependent manner. Moreover, the abundance of LYVE-1⁺CCL24⁺ macrophages and elevated systemic levels of CCL24 were associated with vascular calcification and CAD events. Conclusions: LYVE-1 res-like macrophages, via the secretion of CCL24, promote the transdifferentiation of VSMC to osteogenic-like cells with a possible role in vascular calcification and likely a detrimental role in atherosclerotic plaque destabilization. Full article

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27 pages, 2930 KiB

Open AccessReview

Human iPSC-Cardiomyocytes as an Experimental Model to Study Epigenetic Modifiers of Electrophysiology

by Maria R. Pozo, Gantt W. Meredith and Emilia Entcheva

Cells 2022, 11(2), 200; https://doi.org/10.3390/cells11020200 - 07 Jan 2022

Cited by 9 | Viewed by 4178

Abstract

The epigenetic landscape and the responses to pharmacological epigenetic regulators in each human are unique. Classes of epigenetic writers and erasers, such as histone acetyltransferases, HATs, and histone deacetylases, HDACs, control DNA acetylation/deacetylation and chromatin accessibility, thus exerting transcriptional control in a tissue- [...] Read more.

The epigenetic landscape and the responses to pharmacological epigenetic regulators in each human are unique. Classes of epigenetic writers and erasers, such as histone acetyltransferases, HATs, and histone deacetylases, HDACs, control DNA acetylation/deacetylation and chromatin accessibility, thus exerting transcriptional control in a tissue- and person-specific manner. Rapid development of novel pharmacological agents in clinical testing—HDAC inhibitors (HDACi)—targets these master regulators as common means of therapeutic intervention in cancer and immune diseases. The action of these epigenetic modulators is much less explored for cardiac tissue, yet all new drugs need to be tested for cardiotoxicity. To advance our understanding of chromatin regulation in the heart, and specifically how modulation of DNA acetylation state may affect functional electrophysiological responses, human-induced pluripotent stem-cell-derived cardiomyocyte (hiPSC-CM) technology can be leveraged as a scalable, high-throughput platform with ability to provide patient-specific insights. This review covers relevant background on the known roles of HATs and HDACs in the heart, the current state of HDACi development, applications, and any adverse cardiac events; it also summarizes relevant differential gene expression data for the adult human heart vs. hiPSC-CMs along with initial transcriptional and functional results from using this new experimental platform to yield insights on epigenetic control of the heart. We focus on the multitude of methodologies and workflows needed to quantify responses to HDACis in hiPSC-CMs. This overview can help highlight the power and the limitations of hiPSC-CMs as a scalable experimental model in capturing epigenetic responses relevant to the human heart. Full article

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2021

Jump to: 2024, 2023, 2022

20 pages, 6005 KiB

Open AccessArticle

Pleiotropic Effects of the Protease-Activated Receptor 1 (PAR1) Inhibitor, Vorapaxar, on Atherosclerosis and Vascular Inflammation

by Julian Friebel, Eileen Moritz, Marco Witkowski, Kai Jakobs, Elisabeth Strässler, Andrea Dörner, Daniel Steffens, Marianna Puccini, Stella Lammel, Rainer Glauben, Franziska Nowak, Nicolle Kränkel, Arash Haghikia, Verena Moos, Heinz-Peter Schutheiss, Stephan B. Felix, Ulf Landmesser, Bernhard H. Rauch and Ursula Rauch

Cells 2021, 10(12), 3517; https://doi.org/10.3390/cells10123517 - 13 Dec 2021

Cited by 12 | Viewed by 3165

Abstract

Background: Protease-activated receptor 1 (PAR1) and toll-like receptors (TLRs) are inflammatory mediators contributing to atherogenesis and atherothrombosis. Vorapaxar, which selectively antagonizes PAR1-signaling, is an approved, add-on antiplatelet therapy for secondary prevention. The non-hemostatic, platelet-independent, pleiotropic effects of vorapaxar have not yet been studied. [...] Read more.

Background: Protease-activated receptor 1 (PAR1) and toll-like receptors (TLRs) are inflammatory mediators contributing to atherogenesis and atherothrombosis. Vorapaxar, which selectively antagonizes PAR1-signaling, is an approved, add-on antiplatelet therapy for secondary prevention. The non-hemostatic, platelet-independent, pleiotropic effects of vorapaxar have not yet been studied. Methods and Results: Cellular targets of PAR1 signaling in the vasculature were identified in three patient cohorts with atherosclerotic disease. Evaluation of plasma biomarkers (n = 190) and gene expression in endomyocardial biopsies (EMBs) (n = 12) revealed that PAR1 expression correlated with endothelial activation and vascular inflammation. PAR1 colocalized with TLR2/4 in human carotid plaques and was associated with TLR2/4 gene transcription in EMBs. In addition, vorapaxar reduced atherosclerotic lesion size in apolipoprotein E–knock out (ApoEko) mice. This reduction was associated with reduced expression of vascular adhesion molecules and TLR2/4 presence, both in isolated murine endothelial cells and the aorta. Thrombin-induced uptake of oxLDL was augmented by additional TLR2/4 stimulation and abrogated by vorapaxar. Plaque-infiltrating pro-inflammatory cells were reduced in vorapaxar-treated ApoEko mice. A shift toward M2 macrophages paralleled a decreased transcription of pro-inflammatory cytokines and chemokines. Conclusions: PAR1 inhibition with vorapaxar may be effective in reducing residual thrombo-inflammatory event risk in patients with atherosclerosis independent of its effect on platelets. Full article

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18 pages, 692 KiB

Open AccessReview

Acetyltransferase p300 Is a Putative Epidrug Target for Amelioration of Cellular Aging-Related Cardiovascular Disease

by Asish K. Ghosh

Cells 2021, 10(11), 2839; https://doi.org/10.3390/cells10112839 - 22 Oct 2021

Cited by 11 | Viewed by 3505

Abstract

Cardiovascular disease is the leading cause of accelerated as well as chronological aging-related human morbidity and mortality worldwide. Genetic, immunologic, unhealthy lifestyles including daily consumption of high-carb/high-fat fast food, lack of exercise, drug addiction, cigarette smoke, alcoholism, and exposure to environmental pollutants like [...] Read more.

Cardiovascular disease is the leading cause of accelerated as well as chronological aging-related human morbidity and mortality worldwide. Genetic, immunologic, unhealthy lifestyles including daily consumption of high-carb/high-fat fast food, lack of exercise, drug addiction, cigarette smoke, alcoholism, and exposure to environmental pollutants like particulate matter (PM)-induced stresses contribute profoundly to accelerated and chronological cardiovascular aging and associated life threatening diseases. All these stressors alter gene expression epigenetically either through activation or repression of gene transcription via alteration of chromatin remodeling enzymes and chromatin landscape by DNA methylation or histone methylation or histone acetylation. Acetyltransferase p300, a major epigenetic writer of acetylation on histones and transcription factors, contributes significantly to modifications of chromatin landscape of genes involved in cellular aging and cardiovascular diseases. In this review, the key findings those implicate acetyltransferase p300 as a major contributor to cellular senescence or aging related cardiovascular pathologies including vascular dysfunction, cardiac hypertrophy, myocardial infarction, cardiac fibrosis, systolic/diastolic dysfunction, and aortic valve calcification are discussed. The efficacy of natural or synthetic small molecule inhibitor targeting acetyltransferase p300 in amelioration of stress-induced dysregulated gene expression, cellular aging, and cardiovascular disease in preclinical study is also discussed. Full article

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22 pages, 4016 KiB

Open AccessArticle

Angiotensin II-Induced Long Non-Coding RNA Alivec Regulates Chondrogenesis in Vascular Smooth Muscle Cells

by Vishnu Amaram Samara, Sadhan Das, Marpadga A. Reddy, Vinay Singh Tanwar, Kenneth Stapleton, Amy Leung, Maryam Abdollahi, Rituparna Ganguly, Linda Lanting and Rama Natarajan

Cells 2021, 10(10), 2696; https://doi.org/10.3390/cells10102696 - 09 Oct 2021

Cited by 4 | Viewed by 2818

Abstract

Long non-coding RNAs (lncRNAs) play key roles in Angiotensin II (AngII) signaling but their role in chondrogenic transformation of vascular smooth muscle cells (VSMCs) is unknown. We describe a novel AngII-induced lncRNA Alivec (Angiotensin II-induced lncRNA in VSMCs eliciting chondrogenic phenotype) implicated in [...] Read more.

Long non-coding RNAs (lncRNAs) play key roles in Angiotensin II (AngII) signaling but their role in chondrogenic transformation of vascular smooth muscle cells (VSMCs) is unknown. We describe a novel AngII-induced lncRNA Alivec (Angiotensin II-induced lncRNA in VSMCs eliciting chondrogenic phenotype) implicated in VSMC chondrogenesis. In rat VSMCs, Alivec and the nearby gene Acan, a chondrogenic marker, were induced by growth factors AngII and PDGF and the inflammatory cytokine TNF-α. AngII co-regulated Alivec and Acan through the activation of AngII type1 receptor signaling and Sox9, a master transcriptional regulator of chondrogenesis. Alivec knockdown with GapmeR antisense-oligonucleotides attenuated the expression of AngII-induced chondrogenic marker genes, including Acan, and inhibited the chondrogenic phenotype of VSMCs. Conversely, Alivec overexpression upregulated these genes and promoted chondrogenic transformation. RNA-pulldown coupled to mass-spectrometry identified Tropomyosin-3-alpha and hnRNPA2B1 proteins as Alivec-binding proteins in VSMCs. Furthermore, male rats with AngII-driven hypertension showed increased aortic expression of Alivec and Acan. A putative human ortholog ALIVEC, was induced by AngII in human VSMCs, and this locus was found to harbor the quantitative trait loci affecting blood pressure. Together, these findings suggest that AngII-regulated lncRNA Alivec functions, at least in part, to mediate the AngII-induced chondrogenic transformation of VSMCs implicated in vascular dysfunction and hypertension. Full article

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24 pages, 29211 KiB

Open AccessArticle

Evaluation of Effects of Ractopamine on Cardiovascular, Respiratory, and Locomotory Physiology in Animal Model Zebrafish Larvae

by Kumail Abbas, Ferry Saputra, Michael Edbert Suryanto, Yu-Heng Lai, Jong-Chin Huang, Wen-Hao Yu, Kelvin H.-C. Chen, Ying-Ting Lin and Chung-Der Hsiao

Cells 2021, 10(9), 2449; https://doi.org/10.3390/cells10092449 - 17 Sep 2021

Cited by 7 | Viewed by 3983

Abstract

Ractopamine (RAC) is a beta-adrenoceptor agonist that is used to promote lean and increased food conversion efficiency in livestock. This compound has been considered to be causing behavioral and physiological alterations in livestock like pig. Few studies have addressed the potential non-target effect [...] Read more.

Ractopamine (RAC) is a beta-adrenoceptor agonist that is used to promote lean and increased food conversion efficiency in livestock. This compound has been considered to be causing behavioral and physiological alterations in livestock like pig. Few studies have addressed the potential non-target effect of RAC in aquatic animals. In this study, we aimed to explore the potential physiological response after acute RAC exposure in zebrafish by evaluating multiple endpoints like locomotor activity, oxygen consumption, and cardiovascular performance. Zebrafish larvae were subjected to waterborne RAC exposure at 0.1, 1, 2, 4, or 8 ppm for 24 h, and the corresponding cardiovascular, respiratory, and locomotion activities were monitored and quantified. In addition, we also performed in silico molecular docking for RAC with 10 zebrafish endogenous β-adrenergic receptors to elucidate the potential acting mechanism of RAC. Results show RAC administration can significantly boost locomotor activity, cardiac performance, oxygen consumption, and blood flow rate, but without affecting the cardiac rhythm regularity in zebrafish embryos. Based on structure-based flexible molecular docking, RAC display similar binding affinity to all ten subtypes of endogenous β-adrenergic receptors, from adra1aa to adra2db, which are equivalent to the human one. This result suggests RAC might act as high potency and broad spectrum β-adrenergic receptors agonist on boosting the locomotor activity, cardiac performance, and oxygen consumption in zebrafish. To validate our results, we co-incubated a well-known β-blocker of propranolol (PROP) with RAC. PROP exposure tends to minimize the locomotor hyperactivity, high oxygen consumption, and cardiac rate in zebrafish larvae. In silico structure-based molecular simulation and binding affinity tests show PROP has an overall lower binding affinity than RAC. Taken together, our studies provide solid in vivo evidence to support that RAC plays crucial roles on modulating cardiovascular, respiratory, and locomotory physiology in zebrafish for the first time. In addition, the versatile functions of RAC as β-agonist possibly mediated via receptor competition with PROP as β-antagonist. Full article

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18 pages, 2593 KiB

Open AccessReview

Mechanisms of Fibroblast Activation and Myocardial Fibrosis: Lessons Learned from FB-Specific Conditional Mouse Models

by Prachi Umbarkar, Suma Ejantkar, Sultan Tousif and Hind Lal

Cells 2021, 10(9), 2412; https://doi.org/10.3390/cells10092412 - 14 Sep 2021

Cited by 26 | Viewed by 5652

Abstract

Heart failure (HF) is a leading cause of morbidity and mortality across the world. Cardiac fibrosis is associated with HF progression. Fibrosis is characterized by the excessive accumulation of extracellular matrix components. This is a physiological response to tissue injury. However, uncontrolled fibrosis [...] Read more.

Heart failure (HF) is a leading cause of morbidity and mortality across the world. Cardiac fibrosis is associated with HF progression. Fibrosis is characterized by the excessive accumulation of extracellular matrix components. This is a physiological response to tissue injury. However, uncontrolled fibrosis leads to adverse cardiac remodeling and contributes significantly to cardiac dysfunction. Fibroblasts (FBs) are the primary drivers of myocardial fibrosis. However, until recently, FBs were thought to play a secondary role in cardiac pathophysiology. This review article will present the evolving story of fibroblast biology and fibrosis in cardiac diseases, emphasizing their recent shift from a supporting to a leading role in our understanding of the pathogenesis of cardiac diseases. Indeed, this story only became possible because of the emergence of FB-specific mouse models. This study includes an update on the advancements in the generation of FB-specific mouse models. Regarding the underlying mechanisms of myocardial fibrosis, we will focus on the pathways that have been validated using FB-specific, in vivo mouse models. These pathways include the TGF-β/SMAD3, p38 MAPK, Wnt/β-Catenin, G-protein-coupled receptor kinase (GRK), and Hippo signaling. A better understanding of the mechanisms underlying fibroblast activation and fibrosis may provide a novel therapeutic target for the management of adverse fibrotic remodeling in the diseased heart. Full article

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10 pages, 933 KiB

Open AccessProtocol

Development of Tg(UAS:SEC-Hsa.ANXA5-YFP,myl7:RFP); Casper(roy^−/−,nacre^−/−) Transparent Transgenic In Vivo Zebrafish Model to Study the Cardiomyocyte Function

by Surendra K. Rajpurohit, Aaron Gopal, May Ye Mon, Nikhil G. Patel and Vishal Arora

Cells 2021, 10(8), 1963; https://doi.org/10.3390/cells10081963 - 02 Aug 2021

Cited by 4 | Viewed by 2526

Abstract

The zebrafish provided an excellent platform to study the genetic and molecular approach of cellular phenotype-based cardiac research. We designed a novel protocol to develop the transparent transgenic zebrafish model to study annexin-5 activity in the cardiovascular function by generating homozygous transparent skin [...] Read more.

The zebrafish provided an excellent platform to study the genetic and molecular approach of cellular phenotype-based cardiac research. We designed a novel protocol to develop the transparent transgenic zebrafish model to study annexin-5 activity in the cardiovascular function by generating homozygous transparent skin Casper(roy^−/−,nacre^−/−); myl7:RFP; annexin-5:YFP transgenic zebrafish. The skin pigmentation background of any vertebrate model organism is a major obstruction for in vivo confocal imaging to study the transgenic cellular phenotype-based study. By developing Casper(roy^−/−,nacre^−/−); myl7; annexin-5 transparent transgenic zebrafish strain, we established time-lapse in vivo confocal microscopy to study cellular phenotype/pathologies of cardiomyocytes over time to quantify changes in cardiomyocyte morphology and function over time, comparing control and cardiac injury and cardio-oncology. Casper contributes to the study by integrating a transparent characteristic in adult zebrafish that allows for simpler transparent visualization and observation. The Casper(roy^−/−,nacre^−/−) transgenic progenies developed through cross-breeding with the transgenic strain of Tg(UAS:SEC-Hsa.ANXA5-YFP,myl7:RFP). Confocal and fluorescent microscopy were being used to obtain accurate, precise imaging and to determine fluorescent protein being activated. This study protocol was conducted under two sections; 1.1: Generation of homozygous Tg(UAS:SEC-Hsa.ANXA5-YFP,myl7:RFP); Casper(roy^−/−,nacre^−/−) zebrafish (generation F01-F06) and 1.2: Screening and sorting the transparent transgenic progeny and in vivo imaging to validate cardiac morphology through in vivo confocal imaging. We coined the newly developed strain as Tg(UAS:SEC-Hsa.ANXA5-YFP,myl7:RFP); Casper(roy^−/−,nacre^−/−)^gmc1. Thus, the newly developed strain maintains transparency of the skin throughout the entire life of zebrafish and is capable of application of a non-invasive in vivo imaging process. These novel results provide an in vivo whole organism-based platform to design high-throughput screening and establish a new horizon for drug discovery in cardiac cell death and cardio-oncology therapeutics and treatment. Full article

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14 pages, 3038 KiB

Open AccessFeature PaperReview

Unfathomed Nanomessages to the Heart: Translational Implications of Stem Cell-Derived, Progenitor Cell Exosomes in Cardiac Repair and Regeneration

by Charan Thej and Raj Kishore

Cells 2021, 10(7), 1811; https://doi.org/10.3390/cells10071811 - 17 Jul 2021

Cited by 7 | Viewed by 2680

Abstract

Exosomes formed from the endosomal membranes at the lipid microdomains of multivesicular bodies (MVBs) have become crucial structures responsible for cell communication. This paracrine communication system between a myriad of cell types is essential for maintaining homeostasis and influencing various biological functions in [...] Read more.

Exosomes formed from the endosomal membranes at the lipid microdomains of multivesicular bodies (MVBs) have become crucial structures responsible for cell communication. This paracrine communication system between a myriad of cell types is essential for maintaining homeostasis and influencing various biological functions in immune, vasculogenic, and regenerative cell types in multiple organs in the body, including, but not limited to, cardiac cells and tissues. Characteristically, exosomes are identifiable by common proteins that participate in their biogenesis; however, many different proteins, mRNA, miRNAs, and lipids, have been identified that mediate intercellular communication and elicit multiple functions in other target cells. Although our understanding of exosomes is still limited, the last decade has seen a steep surge in translational studies involving the treatment of cardiovascular diseases with cell-free exosome fractions from cardiomyocytes (CMs), cardiosphere-derived cells (CDCs), endothelial cells (ECs), mesenchymal stromal cells (MSCs), or their combinations. However, most primary cells are difficult to culture in vitro and to generate sufficient exosomes to treat cardiac ischemia or promote cardiac regeneration effectively. Pluripotent stem cells (PSCs) offer the possibility of an unlimited supply of either committed or terminally differentiated cells and their exosomes for treating cardiovascular diseases (CVDs). This review discusses the promising prospects of treating CVDs using exosomes from cardiac progenitor cells (CPCs), endothelial progenitor cells (EPCs), MSCs, and cardiac fibroblasts derived from PSCs. Full article

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16 pages, 1304 KiB

Open AccessReview

Recellularization of Native Tissue Derived Acellular Scaffolds with Mesenchymal Stem Cells

by Ebtehal Ahmed, Tarek Saleh and Meifeng Xu

Cells 2021, 10(7), 1787; https://doi.org/10.3390/cells10071787 - 15 Jul 2021

Cited by 16 | Viewed by 4069

Abstract

The functionalization of decellularized scaffolds is still challenging because of the recellularization-related limitations, including the finding of the most optimal kind of cell(s) and the best way to control their distribution within the scaffolds to generate native mimicking tissues. That is why researchers [...] Read more.

The functionalization of decellularized scaffolds is still challenging because of the recellularization-related limitations, including the finding of the most optimal kind of cell(s) and the best way to control their distribution within the scaffolds to generate native mimicking tissues. That is why researchers have been encouraged to study stem cells, in particular, mesenchymal stem cells (MSCs), as alternative cells to repopulate and functionalize the scaffolds properly. MSCs could be obtained from various sources and have therapeutic effects on a wide range of inflammatory/degenerative diseases. Therefore, in this mini-review, we will discuss the benefits using of MSCs for recellularization, the factors affecting their efficiency, and the drawbacks that may need to be overcome to generate bioengineered transplantable organs. Full article

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18 pages, 3628 KiB

Open AccessArticle

A Switch from Cell-Associated to Soluble PDGF-B Protects against Atherosclerosis, despite Driving Extramedullary Hematopoiesis

by Renée J. H. A. Tillie, Thomas L. Theelen, Kim van Kuijk, Lieve Temmerman, Jenny de Bruijn, Marion Gijbels, Christer Betsholtz, Erik A. L. Biessen and Judith C. Sluimer

Cells 2021, 10(7), 1746; https://doi.org/10.3390/cells10071746 - 10 Jul 2021

Cited by 4 | Viewed by 3486

Abstract

Platelet-derived growth factor B (PDGF-B) is a mitogenic, migratory and survival factor. Cell-associated PDGF-B recruits stabilizing pericytes towards blood vessels through retention in extracellular matrix. We hypothesized that the genetic ablation of cell-associated PDGF-B by retention motif deletion would reduce the local availability [...] Read more.

Platelet-derived growth factor B (PDGF-B) is a mitogenic, migratory and survival factor. Cell-associated PDGF-B recruits stabilizing pericytes towards blood vessels through retention in extracellular matrix. We hypothesized that the genetic ablation of cell-associated PDGF-B by retention motif deletion would reduce the local availability of PDGF-B, resulting in microvascular pericyte loss, microvascular permeability and exacerbated atherosclerosis. Therefore, Ldlr^-/-Pdgfb^ret^/ret mice were fed a high cholesterol diet. Although plaque size was increased in the aortic root of Pdgfb^ret^/ret mice, microvessel density and intraplaque hemorrhage were unexpectedly unaffected. Plaque macrophage content was reduced, which is likely attributable to increased apoptosis, as judged by increased TUNEL+ cells in Pdgfb^ret^/ret plaques (2.1-fold) and increased Pdgfb^ret^/ret macrophage apoptosis upon 7-ketocholesterol or oxidized LDL incubation in vitro. Moreover, Pdgfb^ret^/ret plaque collagen content increased independent of mesenchymal cell density. The decreased macrophage matrix metalloproteinase activity could partly explain Pdgfb^ret^/ret collagen content. In addition to the beneficial vascular effects, we observed reduced body weight gain related to smaller fat deposition in Pdgfb^ret^/ret liver and adipose tissue. While dampening plaque inflammation, Pdgfb^ret^/ret paradoxically induced systemic leukocytosis. The increased incorporation of 5-ethynyl-2′-deoxyuridine indicated increased extramedullary hematopoiesis and the increased proliferation of circulating leukocytes. We concluded that Pdgfb^ret^/ret confers vascular and metabolic effects, which appeared to be protective against diet-induced cardiovascular burden. These effects were unrelated to arterial mesenchymal cell content or adventitial microvessel density and leakage. In contrast, the deletion drives splenic hematopoiesis and subsequent leukocytosis in hypercholesterolemia. Full article

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14 pages, 2509 KiB

Open AccessArticle

The C0-C1f Region of Cardiac Myosin Binding Protein-C Induces Pro-Inflammatory Responses in Fibroblasts via TLR4 Signaling

by Athiththan Yogeswaran, Christian Troidl, James W. McNamara, Jochen Wilhelm, Theresa Truschel, Laila Widmann, Muhammad Aslam, Christian W. Hamm, Sakthivel Sadayappan and Christoph Lipps

Cells 2021, 10(6), 1326; https://doi.org/10.3390/cells10061326 - 26 May 2021

Cited by 6 | Viewed by 3486

Abstract

Myocardial injury is associated with inflammation and fibrosis. Cardiac myosin-binding protein-C (cMyBP-C) is cleaved by µ-calpain upon myocardial injury, releasing C0-C1f, an N-terminal peptide of cMyBP-C. Previously, we reported that the presence of C0-C1f is pathogenic within cardiac tissue and is able [...] Read more.

Myocardial injury is associated with inflammation and fibrosis. Cardiac myosin-binding protein-C (cMyBP-C) is cleaved by µ-calpain upon myocardial injury, releasing C0-C1f, an N-terminal peptide of cMyBP-C. Previously, we reported that the presence of C0-C1f is pathogenic within cardiac tissue and is able to activate macrophages. Fibroblasts also play a crucial role in cardiac remodeling arising from ischemic events, as they contribute to both inflammation and scar formation. To understand whether C0-C1f directly modulates fibroblast phenotype, we analyzed the impact of C0-C1f on a human fibroblast cell line in vitro by performing mRNA microarray screening, immunofluorescence staining, and quantitative real-time PCR. The underlying signaling pathways were investigated by KEGG analysis and determined more precisely by targeted inhibition of the potential signaling cascades in vitro. C0-C1f induced pro-inflammatory responses that might delay TGFβ-mediated myofibroblast conversion. TGFβ also counteracted C0-C1f-mediated fibroblast activation. Inhibition of TLR4 or NFκB as well as the delivery of miR-146 significantly reduced C0-C1f-mediated effects. In conclusion, C0-C1f induces inflammatory responses in human fibroblasts that are mediated via TRL4 signaling, which is decreased in the presence of TGFβ. Specific targeting of TLR4 signaling could be an innovative strategy to modulate C0-C1f-mediated inflammation. Full article

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13 pages, 2339 KiB

Open AccessArticle

In Vivo Stimulation of α- and β-Adrenoceptors in Mice Differentially Alters Small RNA Content of Circulating Extracellular Vesicles

by Jin-Sook Kwon, Eric W. Barr, J. Kurt Chuprun and Walter J. Koch

Cells 2021, 10(5), 1211; https://doi.org/10.3390/cells10051211 - 15 May 2021

Cited by 4 | Viewed by 2280

Abstract

When myocardial function is compromised as in heart failure (HF), there is activation of the sympathetic nervous system with elevated circulating catecholamine levels. These catecholamines activate cardiac and extra-cardiac adrenergic receptors (ARs). Interest in secreted extracellular vesicles (EVs) from the heart is growing [...] Read more.

When myocardial function is compromised as in heart failure (HF), there is activation of the sympathetic nervous system with elevated circulating catecholamine levels. These catecholamines activate cardiac and extra-cardiac adrenergic receptors (ARs). Interest in secreted extracellular vesicles (EVs) from the heart is growing and in HF, it is not known whether excessive activation of α- or β-adrenergic receptors (ARs) could induce specific changes in EV content. In this study, we have evaluated, by next generation sequencing, the small RNA content, including micro-RNAs (miRs), of circulating EVs of mice exposed to chronic selective α- or β- AR stimulation. EVs from mouse blood were purified by differential ultracentrifugation resulting in EVs with an average size of 116.6 ± 4.8 nm that by immunoblotting included protein markers of EVs. We identified the presence of miRs in blood EVs using miR-21-5p and -16-5p real-time PCR as known constituents of blood exosomes that make up a portion of EVs. We next performed next generation sequencing (NGS) of small non-coding RNAs found in blood EVs from mice following 7 days of chronic treatment with isoproterenol (ISO) or phenylephrine (PE) to stimulate α- or β-ARs, respectively. PE increased the percent of genomic repeat region reads and decreased the percent of miR reads. In miR expression analysis, PE and ISO displayed specific patterns of miR expression that suggests differential pathway regulation. The top 20 KEGG pathways predicted by differential expressed miRs show that PE and ISO share 11 of 20 pathways analyzed and reveal also key differences including three synapse relative pathways induced by ISO relative to PE treatment. Both α-and β-AR agonists can alter small RNA content of circulating blood EVs/exosomes including differential expression and loading of miRs that indicate regulation of distinct pathways. This study provides novel insight into chronic sympathetic nervous system activation in HF where excessive catecholamines may not only participate in pathological remodeling of the heart but alter other organs due to secretion of EVs with altered miR content. Full article

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17 pages, 1018 KiB

Open AccessReview

Inflammasome Activation-Induced Hypercoagulopathy: Impact on Cardiovascular Dysfunction Triggered in COVID-19 Patients

by Lealem Gedefaw, Sami Ullah, Polly H. M. Leung, Yin Cai, Shea-Ping Yip and Chien-Ling Huang

Cells 2021, 10(4), 916; https://doi.org/10.3390/cells10040916 - 16 Apr 2021

Cited by 19 | Viewed by 4891

Abstract

Coronavirus disease 2019 (COVID-19) is the most devastating infectious disease in the 21st century with more than 2 million lives lost in less than a year. The activation of inflammasome in the host infected by SARS-CoV-2 is highly related to cytokine storm and [...] Read more.

Coronavirus disease 2019 (COVID-19) is the most devastating infectious disease in the 21st century with more than 2 million lives lost in less than a year. The activation of inflammasome in the host infected by SARS-CoV-2 is highly related to cytokine storm and hypercoagulopathy, which significantly contribute to the poor prognosis of COVID-19 patients. Even though many studies have shown the host defense mechanism induced by inflammasome against various viral infections, mechanistic interactions leading to downstream cellular responses and pathogenesis in COVID-19 remain unclear. The SARS-CoV-2 infection has been associated with numerous cardiovascular disorders including acute myocardial injury, myocarditis, arrhythmias, and venous thromboembolism. The inflammatory response triggered by the activation of NLRP3 inflammasome under certain cardiovascular conditions resulted in hyperinflammation or the modulation of angiotensin-converting enzyme 2 signaling pathways. Perturbations of several target cells and tissues have been described in inflammasome activation, including pneumocytes, macrophages, endothelial cells, and dendritic cells. The interplay between inflammasome activation and hypercoagulopathy in COVID-19 patients is an emerging area to be further addressed. Targeted therapeutics to suppress inflammasome activation may have a positive effect on the reduction of hyperinflammation-induced hypercoagulopathy and cardiovascular disorders occurring as COVID-19 complications. Full article

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16 pages, 5578 KiB

Open AccessArticle

Upregulated Angiogenesis Is Incompetent to Rescue Dilated Cardiomyopathy Phenotype in Mice

by Mohammed Arif, Perwez Alam, Rafeeq PH Ahmed, Raghav Pandey, Hafeez M Faridi and Sakthivel Sadayappan

Cells 2021, 10(4), 771; https://doi.org/10.3390/cells10040771 - 31 Mar 2021

Cited by 2 | Viewed by 2356

Abstract

Dilated cardiomyopathy (DCM) is characterized by pathologic cardiac remodeling resulting in chambers enlargement and impaired heart contractility. Previous reports and our in-silico analysis support the association of DCM phenotype and impaired tissue angiogenesis. Here, we explored whether the modulation in cardiac angiogenesis partly [...] Read more.

Dilated cardiomyopathy (DCM) is characterized by pathologic cardiac remodeling resulting in chambers enlargement and impaired heart contractility. Previous reports and our in-silico analysis support the association of DCM phenotype and impaired tissue angiogenesis. Here, we explored whether the modulation in cardiac angiogenesis partly intervenes or rescues the DCM phenotype in mice. Here, a DCM mouse model [α-tropomyosin 54 (α-TM54) mutant] was crossbred with microRNA-210 transgenic mice (210-TG) to develop microRNA-210 (miR-210) overexpressing α-TM54 mutant mice (TMx210). Contrary to wild-type (WT) and 210-TG mice, a significant increase in heart weight to body weight ratio in aged mixed-gender TMx210 and DCM mice was recorded. Histopathological analysis revealed signs of pathological cardiac remodeling such as myocardial disarray, myofibrillar loss, and interstitial fibrosis in DCM and TMx210 mice. Contrary to WT and DCM, a significant increase in angiogenic potential was observed in TMx210 and 210-TG mice hearts which is reflected by higher blood vessel density and upregulated proangiogenic vascular endothelial growth factor-A. The echocardiographic assessment showed comparable cardiac dysfunction in DCM and TMx210 mice as compared to WT and 210-TG. Overall, the present study concludes that miR-210 mediated upregulated angiogenesis is not sufficient to rescue the DCM phenotype in mice. Full article

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Graphical abstract

20 pages, 3574 KiB

Open AccessReview

Cardiac Cell Therapy for Heart Repair: Should the Cells Be Left Out?

by Dashuai Zhu and Ke Cheng

Cells 2021, 10(3), 641; https://doi.org/10.3390/cells10030641 - 13 Mar 2021

Cited by 23 | Viewed by 4264

Abstract

Cardiovascular disease (CVD) is still the leading cause of death worldwide. Coronary artery occlusion, or myocardial infarction (MI) causes massive loss of cardiomyocytes. The ischemia area is eventually replaced by a fibrotic scar. From the mechanical dysfunctions of the scar in electronic transduction, [...] Read more.

Cardiovascular disease (CVD) is still the leading cause of death worldwide. Coronary artery occlusion, or myocardial infarction (MI) causes massive loss of cardiomyocytes. The ischemia area is eventually replaced by a fibrotic scar. From the mechanical dysfunctions of the scar in electronic transduction, contraction and compliance, pathological cardiac dilation and heart failure develops. Once end-stage heart failure occurs, the only option is to perform heart transplantation. The sequential changes are termed cardiac remodeling, and are due to the lack of endogenous regenerative actions in the adult human heart. Regenerative medicine and biomedical engineering strategies have been pursued to repair the damaged heart and to restore normal cardiac function. Such strategies include both cellular and acellular products, in combination with biomaterials. In addition, substantial progress has been made to elucidate the molecular and cellular mechanisms underlying heart repair and regeneration. In this review, we summarize and discuss current therapeutic approaches for cardiac repair and provide a perspective on novel strategies that holding potential opportunities for future research and clinical translation. Full article

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32 pages, 2192 KiB

Open AccessReview

Molecular and Genetic Profiling for Precision Medicines in Pulmonary Arterial Hypertension

by Shahood Fazal, Malik Bisserier and Lahouaria Hadri

Cells 2021, 10(3), 638; https://doi.org/10.3390/cells10030638 - 13 Mar 2021

Cited by 11 | Viewed by 4450

Abstract

Pulmonary arterial hypertension (PAH) is a rare and chronic lung disease characterized by progressive occlusion of the small pulmonary arteries, which is associated with structural and functional alteration of the smooth muscle cells and endothelial cells within the pulmonary vasculature. Excessive vascular remodeling [...] Read more.

Pulmonary arterial hypertension (PAH) is a rare and chronic lung disease characterized by progressive occlusion of the small pulmonary arteries, which is associated with structural and functional alteration of the smooth muscle cells and endothelial cells within the pulmonary vasculature. Excessive vascular remodeling is, in part, responsible for high pulmonary vascular resistance and the mean pulmonary arterial pressure, increasing the transpulmonary gradient and the right ventricular “pressure overload”, which may result in right ventricular (RV) dysfunction and failure. Current technological advances in multi-omics approaches, high-throughput sequencing, and computational methods have provided valuable tools in molecular profiling and led to the identification of numerous genetic variants in PAH patients. In this review, we summarized the pathogenesis, classification, and current treatments of the PAH disease. Additionally, we outlined the latest next-generation sequencing technologies and the consequences of common genetic variants underlying PAH susceptibility and disease progression. Finally, we discuss the importance of molecular genetic testing for precision medicine in PAH and the future of genomic medicines, including gene-editing technologies and gene therapies, as emerging alternative approaches to overcome genetic disorders in PAH. Full article

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Graphical abstract

25 pages, 10463 KiB

Open AccessArticle

Long-Term Effects of Very Low Dose Particle Radiation on Gene Expression in the Heart: Degenerative Disease Risks

by Venkata Naga Srikanth Garikipati, Arsen Arakelyan, Eleanor A. Blakely, Polly Y. Chang, May M. Truongcao, Maria Cimini, Vandana Malaredy, Anamika Bajpai, Sankar Addya, Malik Bisserier, Agnieszka Brojakowska, Abrisham Eskandari, Mary K. Khlgatian, Lahouaria Hadri, Kenneth M. Fish, Raj Kishore and David. A. Goukassian

Cells 2021, 10(2), 387; https://doi.org/10.3390/cells10020387 - 13 Feb 2021

Cited by 9 | Viewed by 3595

Abstract

Compared to low doses of gamma irradiation (γ-IR), high-charge-and-energy (HZE) particle IR may have different biological response thresholds in cardiac tissue at lower doses, and these effects may be IR type and dose dependent. Three- to four-month-old female CB6F1/Hsd mice were exposed once [...] Read more.

Compared to low doses of gamma irradiation (γ-IR), high-charge-and-energy (HZE) particle IR may have different biological response thresholds in cardiac tissue at lower doses, and these effects may be IR type and dose dependent. Three- to four-month-old female CB6F1/Hsd mice were exposed once to one of four different doses of the following types of radiation: γ-IR ¹³⁷Cs (40-160 cGy, 0.662 MeV), ¹⁴Si-IR (4-32 cGy, 260 MeV/n), or ²²Ti-IR (3-26 cGy, 1 GeV/n). At 16 months post-exposure, animals were sacrificed and hearts were harvested and archived as part of the NASA Space Radiation Tissue Sharing Forum. These heart tissue samples were used in our study for RNA isolation and microarray hybridization. Functional annotation of twofold up/down differentially expressed genes (DEGs) and bioinformatics analyses revealed the following: (i) there were no clear lower IR thresholds for HZE- or γ-IR; (ii) there were 12 common DEGs across all 3 IR types; (iii) these 12 overlapping genes predicted various degrees of cardiovascular, pulmonary, and metabolic diseases, cancer, and aging; and (iv) these 12 genes revealed an exclusive non-linear DEG pattern in ¹⁴Si- and ²²Ti-IR-exposed hearts, whereas two-thirds of γ-IR-exposed hearts revealed a linear pattern of DEGs. Thus, our study may provide experimental evidence of excess relative risk (ERR) quantification of low/very low doses of full-body space-type IR-associated degenerative disease development. Full article

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19 pages, 589 KiB

Open AccessArticle

Genetic Modifiers of Hereditary Neuromuscular Disorders and Cardiomyopathy

by Sholeh Bazrafshan, Hani Kushlaf, Mashhood Kakroo, John Quinlan, Richard C. Becker and Sakthivel Sadayappan

Cells 2021, 10(2), 349; https://doi.org/10.3390/cells10020349 - 08 Feb 2021

Cited by 4 | Viewed by 3366

Abstract

Novel genetic variants exist in patients with hereditary neuromuscular disorders (NMD), including muscular dystrophy. These patients also develop cardiac manifestations. However, the association between these gene variants and cardiac abnormalities is understudied. To determine genetic modifiers and features of cardiac disease in NMD [...] Read more.

Novel genetic variants exist in patients with hereditary neuromuscular disorders (NMD), including muscular dystrophy. These patients also develop cardiac manifestations. However, the association between these gene variants and cardiac abnormalities is understudied. To determine genetic modifiers and features of cardiac disease in NMD patients, we have reviewed electronic medical records of 651 patients referred to the Muscular Dystrophy Association Care Center at the University of Cincinnati and characterized the clinical phenotype of 14 patients correlating with their next-generation sequencing data. The data were retrieved from the electronic medical records of the 14 patients included in the current study and comprised neurologic and cardiac phenotype and genetic reports which included comparative genomic hybridization array and NGS. Novel associations were uncovered in the following eight patients diagnosed with Limb-girdle Muscular Dystrophy, Bethlem Myopathy, Necrotizing Myopathy, Charcot-Marie-Tooth Disease, Peripheral Polyneuropathy, and Valosin-containing Protein-related Myopathy. Mutations in COL6A1, COL6A3, SGCA, SYNE1, FKTN, PLEKHG5, ANO5, and SMCHD1 genes were the most common, and the associated cardiac features included bundle branch blocks, ventricular chamber dilation, septal thickening, and increased outflow track gradients. Our observations suggest that features of cardiac disease and modifying gene mutations in patients with NMD require further investigation to better characterize genotype–phenotype relationships. Full article

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