Research

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19 pages, 2074 KiB

Open AccessArticle

GPR91 Receptor Mediates Protection against Doxorubicin-Induced Cardiotoxicity without Altering Its Anticancer Efficacy. An In Vitro Study on H9C2 Cardiomyoblasts and Breast Cancer-Derived MCF-7 Cells

by Matthieu Dallons, Esma Alpan, Corentin Schepkens, Vanessa Tagliatti and Jean-Marie Colet

Cells 2020, 9(10), 2177; https://doi.org/10.3390/cells9102177 - 27 Sep 2020

Cited by 6 | Viewed by 2998

Abstract

Doxorubicin (DOX) is an anticancer drug widely used in oncology, especially for breast cancer. The main limitation of DOX treatment is its cardiotoxicity due to the cumulative dose. Clinically, DOX-induced cardiomyopathy develops as a progressive heart failure caused by a progressive cardiomyocyte’s death. [...] Read more.

Doxorubicin (DOX) is an anticancer drug widely used in oncology, especially for breast cancer. The main limitation of DOX treatment is its cardiotoxicity due to the cumulative dose. Clinically, DOX-induced cardiomyopathy develops as a progressive heart failure caused by a progressive cardiomyocyte’s death. For long, the oxidative stress induced by DOX was considered as the main toxic mechanism responsible for heart damage, but it is now controverted, and other processes are investigated to develop cardioprotective strategies. Previously, we studied DOX-induced cardiotoxicity and dexrazoxane (DEX), the only cardioprotective compound authorized by the FDA, by ¹H-NMR metabonomics in H9C2 cells. We observed an increased succinate secretion in the extracellular fluid of DEX-exposed cardiomyocytes, a finding that led us to the hypothesis of a possible protective role of this agonist of the GPR91 receptor. The objective of the present work was to study the effect of succinate (SUC) and cis-epoxysuccinate (cis-ES), two agonists of the GPR91 receptor, on DOX-induced cardiotoxicity to H9C2 cells. To this purpose, several toxicity parameters, including cell viability, oxidative stress and apoptosis, as well as the GPR91 expression, were measured to assess the effects of DEX, SUC and cis-ES either alone or in combination with DOX in H9C2 cells. A ¹H-NMR-based metabonomic study was carried out on cellular fluids collected after 24 h to highlight the metabolic changes induced by those protective compounds. Moreover, the effects of each agonist given either alone or in combination with DOX were evaluated on MCF-7 breast cancer cells. GPR91 expression was confirmed in H9C2 cells, while no expression was found in MCF-7 cells. Under such experimental conditions, both SUC and cis-ES decreased partially the cellular mortality, the oxidative stress and the apoptosis induced by DOX. The SUC protective effect was similar to the DEX effect, but the protective effect of cis-ES was higher on oxidative stress and apoptosis. In addition, the metabonomics findings pointed out several metabolic pathways involved in the cardioprotective effects of both GPR91 agonists: the stimulation of aerobic metabolism with glucose as the main fuel, redox balance and phospholipids synthesis. Finally, none of the GPR91 agonists jeopardized the pharmacological effects of DOX on MCF-7 breast cancer cells. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis of Cardiovascular Disease)

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21 pages, 3840 KiB

Open AccessArticle

Integrative Multi-Omics Analysis in Calcific Aortic Valve Disease Reveals a Link to the Formation of Amyloid-Like Deposits

by Marina A. Heuschkel, Nikolaos T. Skenteris, Joshua D. Hutcheson, Dewy D. van der Valk, Juliane Bremer, Philip Goody, Jesper Hjortnaes, Felix Jansen, Carlijn V.C. Bouten, Antoon van den Bogaerdt, Ljubica Matic, Nikolaus Marx and Claudia Goettsch

Cells 2020, 9(10), 2164; https://doi.org/10.3390/cells9102164 - 24 Sep 2020

Cited by 15 | Viewed by 5390

Abstract

Calcific aortic valve disease (CAVD) is the most prevalent valvular heart disease in the developed world, yet no pharmacological therapy exists. Here, we hypothesize that the integration of multiple omic data represents an approach towards unveiling novel molecular networks in CAVD. Databases were [...] Read more.

Calcific aortic valve disease (CAVD) is the most prevalent valvular heart disease in the developed world, yet no pharmacological therapy exists. Here, we hypothesize that the integration of multiple omic data represents an approach towards unveiling novel molecular networks in CAVD. Databases were searched for CAVD omic studies. Differentially expressed molecules from calcified and control samples were retrieved, identifying 32 micro RNAs (miRNA), 596 mRNAs and 80 proteins. Over-representation pathway analysis revealed platelet degranulation and complement/coagulation cascade as dysregulated pathways. Multi-omics integration of overlapping proteome/transcriptome molecules, with the miRNAs, identified a CAVD protein–protein interaction network containing seven seed genes (apolipoprotein A1 (APOA1), hemoglobin subunit β (HBB), transferrin (TF), α-2-macroglobulin (A2M), transforming growth factor β-induced protein (TGFBI), serpin family A member 1 (SERPINA1), lipopolysaccharide binding protein (LBP), inter-α-trypsin inhibitor heavy chain 3 (ITIH3) and immunoglobulin κ constant (IGKC)), four input miRNAs (miR-335-5p, miR-3663-3p, miR-21-5p, miR-93-5p) and two connector genes (amyloid beta precursor protein (APP) and transthyretin (TTR)). In a metabolite–gene–disease network, Alzheimer’s disease exhibited the highest degree of betweenness. To further strengthen the associations based on the multi-omics approach, we validated the presence of APP and TTR in calcified valves from CAVD patients by immunohistochemistry. Our study suggests a novel molecular CAVD network potentially linked to the formation of amyloid-like structures. Further investigations on the associated mechanisms and therapeutic potential of targeting amyloid-like deposits in CAVD may offer significant health benefits. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis of Cardiovascular Disease)

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16 pages, 2468 KiB

Open AccessArticle

The Expression of microRNA in Adult Rat Heart with Isoproterenol-Induced Cardiac Hypertrophy

by Mailin Gan, Shunhua Zhang, Yuan Fan, Ya Tan, Zhixian Guo, Lei Chen, Lin Bai, Dongmei Jiang, Xiaoxia Hao, Xuewei Li, Linyuan Shen and Li Zhu

Cells 2020, 9(5), 1173; https://doi.org/10.3390/cells9051173 - 08 May 2020

Cited by 8 | Viewed by 3539

Abstract

Cardiac hypertrophy is a common pathological condition and an independent risk factor that triggers cardiovascular morbidity. As an important epigenetic regulator, miRNA is widely involved in many biological processes. In this study, miRNAs expressed in rat hearts that underwent isoprenaline-induced cardiac hypertrophy were [...] Read more.

Cardiac hypertrophy is a common pathological condition and an independent risk factor that triggers cardiovascular morbidity. As an important epigenetic regulator, miRNA is widely involved in many biological processes. In this study, miRNAs expressed in rat hearts that underwent isoprenaline-induced cardiac hypertrophy were identified using high-throughput sequencing, and functional verification of typical miRNAs was performed using rat primary cardiomyocytes. A total of 623 miRNAs were identified, of which 33 were specifically expressed in cardiac hypertrophy rats. The enriched pathways of target genes of differentially expressed miRNAs included the FoxO signaling pathway, dopaminergic synapse, Wnt signaling pathway, MAPK (mitogen-activated protein kinase) signaling pathway, and Hippo signaling pathway. Subsequently, miR-144 was the most differentially expressed miRNA and was subsequently selected for in vitro validation. Inhibition of miR-144 expression in primary myocardial cells caused up-regulation of cardiac hypertrophy markers atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). The dual luciferase reporter system showed that ANP may be a target gene of miR-144. Long non-coding RNA myocardial infarction associated transcript (LncMIAT) is closely related to heart disease, and here, we were the first to discover that LncMIAT may act as an miR-144 sponge in isoproterenol-induced cardiac hypertrophy. Taken together, these results enriched the understanding of miRNA in regulating cardiac hypertrophy and provided a reference for preventing and treating cardiac hypertrophy. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis of Cardiovascular Disease)

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17 pages, 2491 KiB

Open AccessArticle

Lack of PCSK6 Increases Flow-Mediated Outward Arterial Remodeling in Mice

by Samuel Röhl, Bianca E. Suur, Mariette Lengquist, Till Seime, Kenneth Caidahl, Ulf Hedin, Anders Arner, Ljubica Matic and Anton Razuvaev

Cells 2020, 9(4), 1009; https://doi.org/10.3390/cells9041009 - 18 Apr 2020

Cited by 5 | Viewed by 2957

Abstract

Proprotein convertases (PCSKs) process matrix metalloproteases and cytokines, but their function in the vasculature is largely unknown. Previously, we demonstrated upregulation of PCSK6 in atherosclerotic plaques from symptomatic patients, localization to smooth muscle cells (SMCs) in the fibrous cap and positive correlations with [...] Read more.

Proprotein convertases (PCSKs) process matrix metalloproteases and cytokines, but their function in the vasculature is largely unknown. Previously, we demonstrated upregulation of PCSK6 in atherosclerotic plaques from symptomatic patients, localization to smooth muscle cells (SMCs) in the fibrous cap and positive correlations with inflammation, extracellular matrix remodeling and cytokines. Here, we hypothesize that PCSK6 could be involved in flow-mediated vascular remodeling and aim to evaluate its role in the physiology of this process using knockout mice. Pcsk6^−/− and wild type mice were randomized into control and increased blood flow groups and induced in the right common carotid artery (CCA) by ligation of the left CCA. The animals underwent repeated ultrasound biomicroscopy (UBM) examinations followed by euthanization with subsequent evaluation using wire myography, transmission electron microscopy or histology. The Pcsk6^−/− mice displayed a flow-mediated increase in lumen circumference over time, assessed with UBM. Wire myography revealed differences in the flow-mediated remodeling response detected as an increase in lumen circumference at optimal stretch with concomitant reduction in active tension. Furthermore, a flow-mediated reduction in expression of SMC contractile markers SMA, MYH11 and LMOD1 was seen in the Pcsk6^−/− media. Absence of PCSK6 increases outward remodeling and reduces medial contractility in response to increased blood flow. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis of Cardiovascular Disease)

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16 pages, 4133 KiB

Open AccessArticle

Haploinsufficient Rock1^+/− and Rock2^+/− Mice Are Not Protected from Cardiac Inflammation and Postinflammatory Fibrosis in Experimental Autoimmune Myocarditis

by Karolina Tkacz, Filip Rolski, Marcin Czepiel, Edyta Działo, Maciej Siedlar, Urs Eriksson, Gabriela Kania and Przemysław Błyszczuk

Cells 2020, 9(3), 700; https://doi.org/10.3390/cells9030700 - 12 Mar 2020

Cited by 6 | Viewed by 3329

Abstract

Progressive cardiac fibrosis is a common cause of heart failure. Rho-associated, coiled-coil-containing protein kinases (ROCKs) have been shown to enhance fibrotic processes in the heart and in other organs. In this study, using wild-type, Rock1^+/− and Rock2^+/− haploinsufficient mice and mouse [...] Read more.

Progressive cardiac fibrosis is a common cause of heart failure. Rho-associated, coiled-coil-containing protein kinases (ROCKs) have been shown to enhance fibrotic processes in the heart and in other organs. In this study, using wild-type, Rock1^+/− and Rock2^+/− haploinsufficient mice and mouse model of experimental autoimmune myocarditis (EAM) we addressed the role of ROCK1 and ROCK2 in development of myocarditis and postinflammatory fibrosis. We found that myocarditis severity was comparable in wild-type, Rock1^+/− and Rock2^+/− mice at day 21 of EAM. During the acute stage of the disease, hearts of Rock1^+/− mice showed unaffected numbers of CD11b⁺CD36⁺ macrophages, CD11b⁺CD36^–Ly6G^hiLy6c^hi neutrophils, CD11b⁺CD36^–Ly6G^–Ly6c^hi inflammatory monocytes, CD11b⁺CD36^–Ly6G^–Ly6c^– monocytes, CD11b⁺SiglecF⁺ eosinophils, CD11b⁺CD11c⁺ inflammatory dendritic cells and type I collagen-producing fibroblasts. Isolated Rock1^+/− cardiac fibroblasts treated with transforming growth factor-beta (TGF-β) showed attenuated Smad2 and extracellular signal-regulated kinase (Erk) phosphorylations that were associated with impaired upregulation of smooth muscle actin alpha (αSMA) protein. In contrast to cardiac fibroblasts, expanded Rock1^+/− heart inflammatory myeloid cells showed unaffected Smad2 activation but enhanced Erk phosphorylation following TGF-β treatment. Rock1^+/− inflammatory cells responded to TGF-β by a reduced transcriptional profibrotic response and failed to upregulate αSMA and fibronectin at the protein levels. Unexpectedly, in the EAM model wild-type, Rock1^+/− and Rock2^+/− mice developed a similar extent of cardiac fibrosis at day 40. In addition, hearts of the wild-type and Rock1^+/− mice showed comparable levels of cardiac vimentin, periostin and αSMA. In conclusion, despite the fact that ROCK1 regulates TGF-β-dependent profibrotic response, neither ROCK1 nor ROCK2 is critically involved in the development of postinflammatory fibrosis in the EAM model. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis of Cardiovascular Disease)

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11 pages, 2062 KiB

Open AccessArticle

Proteoglycan 4 is Increased in Human Calcified Aortic Valves and Enhances Valvular Interstitial Cell Calcification

by Gonzalo Artiach, Miguel Carracedo, Till Seime, Oscar Plunde, Andres Laguna-Fernandez, Ljubica Matic, Anders Franco-Cereceda and Magnus Bäck

Cells 2020, 9(3), 684; https://doi.org/10.3390/cells9030684 - 11 Mar 2020

Cited by 18 | Viewed by 3882

Abstract

Aortic valve stenosis (AVS), a consequence of increased fibrosis and calcification of the aortic valve leaflets, causes progressive narrowing of the aortic valve. Proteoglycans, structural components of the aortic valve, accumulate in regions with fibrosis and moderate calcification. Particularly, proteoglycan 4 (PRG4) has [...] Read more.

Aortic valve stenosis (AVS), a consequence of increased fibrosis and calcification of the aortic valve leaflets, causes progressive narrowing of the aortic valve. Proteoglycans, structural components of the aortic valve, accumulate in regions with fibrosis and moderate calcification. Particularly, proteoglycan 4 (PRG4) has been identified in fibrotic parts of aortic valves. However, the role of PRG4 in the context of AVS and aortic valve calcification has not yet been determined. Here, transcriptomics, histology, and immunohistochemistry were performed in human aortic valves from patients undergoing aortic valve replacement. Human valve interstitial cells (VICs) were used for calcification experiments and RNA expression analysis. PRG4 was significantly upregulated in thickened and calcified regions of aortic valves compared with healthy regions. In addition, mRNA levels of PRG4 positively associated with mRNA for proteins involved in cardiovascular calcification. Treatment of VICs with recombinant human PRG4 enhanced phosphate-induced calcification and increased the mRNA expression of bone morphogenetic protein 2 and the runt-related transcription factor 2. In summary, PRG4 was upregulated in the development of AVS and promoted VIC osteogenic differentiation and calcification. These results suggest that an altered valve leaflet proteoglycan composition may play a role in the progression of AVS. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis of Cardiovascular Disease)

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17 pages, 4223 KiB

Open AccessArticle

Calcitriol Attenuates Doxorubicin-Induced Cardiac Dysfunction and Inhibits Endothelial-to-Mesenchymal Transition in Mice

by Tzu-Hsien Tsai, Cheng-Jei Lin, Chi-Ling Hang and Wei-Yu Chen

Cells 2019, 8(8), 865; https://doi.org/10.3390/cells8080865 - 09 Aug 2019

Cited by 31 | Viewed by 5472

Abstract

Doxorubicin (Dox) is an effective anti-neoplasm drug, but its cardiac toxicity limits its clinical use. Endothelial-to-mesenchymal transition (EndMT) has been found to be involved in the process of heart failure. It is unclear whether EndMT contributes to Dox-induced cardiomyopathy (DoIC). Calcitriol, an active [...] Read more.

Doxorubicin (Dox) is an effective anti-neoplasm drug, but its cardiac toxicity limits its clinical use. Endothelial-to-mesenchymal transition (EndMT) has been found to be involved in the process of heart failure. It is unclear whether EndMT contributes to Dox-induced cardiomyopathy (DoIC). Calcitriol, an active form Vitamin D3, blocks the growth of cancer cells by inhibiting the Smad pathway. To investigate the effect of calcitriol via inhibiting EndMT in DoIC, C57BL/6 mice and endothelial-specific labeled mice were intraperitoneally administered Dox twice weekly for 4 weeks (32 mg/kg cumulative dose) and were subsequently treated with or without calcitriol for 12 weeks. Echocardiography revealed diastolic dysfunction at 13 weeks following the first Dox treatment, accompanied by increased myocardial fibrosis and up-regulated pro-fibrotic proteins. Calcitriol attenuated Dox-induced myocardial fibrosis, down-regulated pro-fibrotic proteins and improved diastolic function. Endothelial fate tracing revealed that EndMT-derived cells contributed to Dox-induced cardiac fibrosis. In vitro, human umbilical vein endothelial cells and mouse cardiac fibroblasts were treated with Transforming growth factor (TGF)-β with or without calcitriol. Morphological, immunofluorescence staining, and Western blot analyses revealed that TGF-β-induced EndMT and fibroblast-to-myofibroblast transition (FMT) were attenuated by calcitriol by the inhibition of the Smad2 pathway. Collectively, calcitriol attenuated DoIC through the inhibition of the EndMT and FMT processes. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis of Cardiovascular Disease)

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17 pages, 16854 KiB

Open AccessArticle

Liraglutide Inhibits Endothelial-to-Mesenchymal Transition and Attenuates Neointima Formation after Endovascular Injury in Streptozotocin-Induced Diabetic Mice

by Tzu-Hsien Tsai, Chien-Ho Lee, Cheng-I Cheng, Yen-Nan Fang, Sheng-Ying Chung, Shyh-Ming Chen, Cheng-Jei Lin, Chiung-Jen Wu, Chi-Ling Hang and Wei-Yu Chen

Cells 2019, 8(6), 589; https://doi.org/10.3390/cells8060589 - 14 Jun 2019

Cited by 29 | Viewed by 5181

Abstract

Hyperglycaemia causes endothelial dysfunction, which is the initial process in the development of diabetic vascular complications. Upon injury, endothelial cells undergo an endothelial-to-mesenchymal transition (EndMT), lose their specific marker, and gain mesenchymal phenotypes. This study investigated the effect of liraglutide, a glucagon-like peptide [...] Read more.

Hyperglycaemia causes endothelial dysfunction, which is the initial process in the development of diabetic vascular complications. Upon injury, endothelial cells undergo an endothelial-to-mesenchymal transition (EndMT), lose their specific marker, and gain mesenchymal phenotypes. This study investigated the effect of liraglutide, a glucagon-like peptide 1 (GLP-1) receptor agonist, on EndMT inhibition and neointima formation in diabetic mice induced by streptozotocin. The diabetic mice with a wire-induced vascular injury in the right carotid artery were treated with or without liraglutide for four weeks. The degree of neointima formation and re-endothelialisation was evaluated by histological assessments. Endothelial fate tracing revealed that endothelium-derived cells contribute to neointima formation through EndMT in vivo. In the diabetic mouse model, liraglutide attenuated wire injury-induced neointima formation and accelerated re-endothelialisation. In vitro, a high glucose condition (30 mmol/L) triggered morphological changes and mesenchymal marker expression in human umbilical vein endothelial cells (HUVECs), which were attenuated by liraglutide or Activin receptor-like 5 (ALK5) inhibitor SB431542. The inhibition of AMP-activated protein kinase (AMPK) signaling by Compound C diminished the liraglutide-mediated inhibitory effect on EndMT. Collectively, liraglutide was found to attenuate neointima formation in diabetic mice partially through EndMT inhibition, extending the potential therapeutic role of liraglutide. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis of Cardiovascular Disease)

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18 pages, 2571 KiB

Open AccessEditor’s ChoiceArticle

MAGI1 Mediates eNOS Activation and NO Production in Endothelial Cells in Response to Fluid Shear Stress

by Kedar Ghimire, Jelena Zaric, Begoña Alday-Parejo, Jochen Seebach, Mélanie Bousquenaud, Jimmy Stalin, Grégory Bieler, Hans-Joachim Schnittler and Curzio Rüegg

Cells 2019, 8(5), 388; https://doi.org/10.3390/cells8050388 - 27 Apr 2019

Cited by 34 | Viewed by 7393

Abstract

Fluid shear stress stimulates endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) production through multiple kinases, including protein kinase A (PKA), AMP-activated protein kinase (AMPK), AKT and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII). Membrane-associated guanylate kinase (MAGUK) with inverted domain [...] Read more.

Fluid shear stress stimulates endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) production through multiple kinases, including protein kinase A (PKA), AMP-activated protein kinase (AMPK), AKT and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII). Membrane-associated guanylate kinase (MAGUK) with inverted domain structure-1 (MAGI1) is an adaptor protein that stabilizes epithelial and endothelial cell-cell contacts. The aim of this study was to assess the unknown role of endothelial cell MAGI1 in response to fluid shear stress. We show constitutive expression and co-localization of MAGI1 with vascular endothelial cadherin (VE-cadherin) in endothelial cells at cellular junctions under static and laminar flow conditions. Fluid shear stress increases MAGI1 expression. MAGI1 silencing perturbed flow-dependent responses, specifically, Krüppel-like factor 4 (KLF4) expression, endothelial cell alignment, eNOS phosphorylation and NO production. MAGI1 overexpression had opposite effects and induced phosphorylation of PKA, AMPK, and CAMKII. Pharmacological inhibition of PKA and AMPK prevented MAGI1-mediated eNOS phosphorylation. Consistently, MAGI1 silencing and PKA inhibition suppressed the flow-induced NO production. Endothelial cell-specific transgenic expression of MAGI1 induced PKA and eNOS phosphorylation in vivo and increased NO production ex vivo in isolated endothelial cells. In conclusion, we have identified endothelial cell MAGI1 as a previously unrecognized mediator of fluid shear stress-induced and PKA/AMPK dependent eNOS activation and NO production. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis of Cardiovascular Disease)

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Review

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27 pages, 2675 KiB

Open AccessReview

Effect of Interventions in WNT Signaling on Healing of Cardiac Injury: A Systematic Review

by Evangelos P. Daskalopoulos and W. Matthijs Blankesteijn

Cells 2021, 10(2), 207; https://doi.org/10.3390/cells10020207 - 21 Jan 2021

Cited by 11 | Viewed by 2651

Abstract

The wound healing that follows myocardial infarction is a complex process involving multiple mechanisms, such as inflammation, angiogenesis and fibrosis. In the last two decades, the involvement of WNT signaling has been extensively studied and effects on virtually all aspects of this wound [...] Read more.

The wound healing that follows myocardial infarction is a complex process involving multiple mechanisms, such as inflammation, angiogenesis and fibrosis. In the last two decades, the involvement of WNT signaling has been extensively studied and effects on virtually all aspects of this wound healing have been reported. However, as often is the case in a newly emerging field, inconsistent and sometimes even contradictory findings have been reported. The aim of this systematic review is to provide a comprehensive overview of studies in which the effect of interventions in WNT signaling were investigated in in vivo models of cardiac injury. To this end, we used different search engines to perform a systematic search of the literature using the key words “WNT and myocardial and infarction”. We categorized the interventions according to their place in the WNT signaling pathway (ligand, receptor, destruction complex or nuclear level). The most consistent improvements of the wound healing response were observed in studies in which the acylation of WNT proteins was inhibited by administering porcupine inhibitors, by inhibiting of the downstream glycogen synthase kinase-3β (GSK3β) and by intervening in the β-catenin-mediated gene transcription. Interestingly, in several of these studies, evidence was presented for activation of cardiomyocyte proliferation around the infarct area. These findings indicate that inhibition of WNT signaling can play a valuable role in the repair of cardiac injury, thereby improving cardiac function and preventing the development of heart failure. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis of Cardiovascular Disease)

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27 pages, 2023 KiB

Open AccessReview

The Interplay of WNT and PPARγ Signaling in Vascular Calcification

by Stefan Reinhold, W. Matthijs Blankesteijn and Sébastien Foulquier

Cells 2020, 9(12), 2658; https://doi.org/10.3390/cells9122658 - 10 Dec 2020

Cited by 15 | Viewed by 4858

Abstract

Vascular calcification (VC), the ectopic deposition of calcium phosphate crystals in the vessel wall, is one of the primary contributors to cardiovascular death. The pathology of VC is determined by vascular topography, pre-existing diseases, and our genetic heritage. VC evolves from inflammation, mediated [...] Read more.

Vascular calcification (VC), the ectopic deposition of calcium phosphate crystals in the vessel wall, is one of the primary contributors to cardiovascular death. The pathology of VC is determined by vascular topography, pre-existing diseases, and our genetic heritage. VC evolves from inflammation, mediated by macrophages, and from the osteochondrogenic transition of vascular smooth muscle cells (VSMC) in the atherosclerotic plaque. This pathologic transition partly resembles endochondral ossification, involving the chronologically ordered activation of the β-catenin-independent and -dependent Wingless and Int-1 (WNT) pathways and the termination of peroxisome proliferator-activated receptor γ (PPARγ) signal transduction. Several atherosclerotic plaque studies confirmed the differential activity of PPARγ and the WNT signaling pathways in VC. Notably, the actively regulated β-catenin-dependent and -independent WNT signals increase the osteochondrogenic transformation of VSMC through the up-regulation of the osteochondrogenic transcription factors SRY-box transcription factor 9 (SOX9) and runt-related transcription factor 2 (RUNX2). In addition, we have reported studies showing that WNT signaling pathways may be antagonized by PPARγ activation via the expression of different families of WNT inhibitors and through its direct interaction with β-catenin. In this review, we summarize the existing knowledge on WNT and PPARγ signaling and their interplay during the osteochondrogenic differentiation of VSMC in VC. Finally, we discuss knowledge gaps on this interplay and its possible clinical impact. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis of Cardiovascular Disease)

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15 pages, 1701 KiB

Open AccessReview

A Systematic Review of WNT Signaling in Endothelial Cell Oligodendrocyte Interactions: Potential Relevance to Cerebral Small Vessel Disease

by Narek Manukjan, Zubair Ahmed, Daniel Fulton, W. Matthijs Blankesteijn and Sébastien Foulquier

Cells 2020, 9(6), 1545; https://doi.org/10.3390/cells9061545 - 25 Jun 2020

Cited by 18 | Viewed by 4348

Abstract

Key pathological features of cerebral small vessel disease (cSVD) include impairment of the blood brain barrier (BBB) and the progression of white matter lesions (WMLs) amongst other structural lesions, leading to the clinical manifestations of cSVD. The function of endothelial cells (ECs) is [...] Read more.

Key pathological features of cerebral small vessel disease (cSVD) include impairment of the blood brain barrier (BBB) and the progression of white matter lesions (WMLs) amongst other structural lesions, leading to the clinical manifestations of cSVD. The function of endothelial cells (ECs) is of major importance to maintain a proper BBB. ECs interact with several cell types to provide structural and functional support to the brain. Oligodendrocytes (OLs) myelinate axons in the central nervous system and are crucial in sustaining the integrity of white matter. The interplay between ECs and OLs and their precursor cells (OPCs) has received limited attention yet seems of relevance for the study of BBB dysfunction and white matter injury in cSVD. Emerging evidence shows a crosstalk between ECs and OPCs/OLs, mediated by signaling through the Wingless and Int-1 (WNT)/β-catenin pathway. As the latter is involved in EC function (e.g., angiogenesis) and oligodendrogenesis, we reviewed the role of WNT/β-catenin signaling for both cell types and performed a systematic search to identify studies describing a WNT-mediated interplay between ECs and OPCs/OLs. Dysregulation of this interaction may limit remyelination of WMLs and render the BBB leaky, thereby initiating a vicious neuroinflammatory cycle. A better understanding of the role of this signaling pathway in EC–OL crosstalk is essential in understanding cSVD development. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis of Cardiovascular Disease)

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22 pages, 3107 KiB

Open AccessEditor’s ChoiceReview

Cellular and Molecular Differences between HFpEF and HFrEF: A Step Ahead in an Improved Pathological Understanding

by Steven J. Simmonds, Ilona Cuijpers, Stephane Heymans and Elizabeth A. V. Jones

Cells 2020, 9(1), 242; https://doi.org/10.3390/cells9010242 - 18 Jan 2020

Cited by 161 | Viewed by 22293

Abstract

Heart failure (HF) is the most rapidly growing cardiovascular health burden worldwide. HF can be classified into three groups based on the percentage of the ejection fraction (EF): heart failure with reduced EF (HFrEF), heart failure with mid-range—also called mildly reduced EF— (HFmrEF), [...] Read more.

Heart failure (HF) is the most rapidly growing cardiovascular health burden worldwide. HF can be classified into three groups based on the percentage of the ejection fraction (EF): heart failure with reduced EF (HFrEF), heart failure with mid-range—also called mildly reduced EF— (HFmrEF), and heart failure with preserved ejection fraction (HFpEF). HFmrEF can progress into either HFrEF or HFpEF, but its phenotype is dominated by coronary artery disease, as in HFrEF. HFrEF and HFpEF present with differences in both the development and progression of the disease secondary to changes at the cellular and molecular level. While recent medical advances have resulted in efficient and specific treatments for HFrEF, these treatments lack efficacy for HFpEF management. These differential response rates, coupled to increasing rates of HF, highlight the significant need to understand the unique pathogenesis of HFrEF and HFpEF. In this review, we summarize the differences in pathological development of HFrEF and HFpEF, focussing on disease-specific aspects of inflammation and endothelial function, cardiomyocyte hypertrophy and death, alterations in the giant spring titin, and fibrosis. We highlight the areas of difference between the two diseases with the aim of guiding research efforts for novel therapeutics in HFrEF and HFpEF. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis of Cardiovascular Disease)

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22 pages, 1976 KiB

Open AccessReview

MicroRNAs in Cardiac Diseases

by Robin M.W. Colpaert and Martina Calore

Cells 2019, 8(7), 737; https://doi.org/10.3390/cells8070737 - 18 Jul 2019

Cited by 126 | Viewed by 8183

Abstract

Since their discovery 20 years ago, microRNAs have been related to posttranscriptional regulation of gene expression in major cardiac physiological and pathological processes. We know now that cardiac muscle phenotypes are tightly regulated by multiple noncoding RNA species to maintain cardiac homeostasis. Upon [...] Read more.

Since their discovery 20 years ago, microRNAs have been related to posttranscriptional regulation of gene expression in major cardiac physiological and pathological processes. We know now that cardiac muscle phenotypes are tightly regulated by multiple noncoding RNA species to maintain cardiac homeostasis. Upon stress or various pathological conditions, this class of non-coding RNAs has been found to modulate different cardiac pathological conditions, such as contractility, arrhythmia, myocardial infarction, hypertrophy, and inherited cardiomyopathies. This review summarizes and updates microRNAs playing a role in the different processes underlying the pathogenic phenotypes of cardiac muscle and highlights their potential role as disease biomarkers and therapeutic targets. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis of Cardiovascular Disease)

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