Editorial

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Open AccessEditorial

Molecular Mechanisms of Cardiac Development and Disease

by Nicole Wagner and Kay-Dietrich Wagner

Int. J. Mol. Sci. 2023, 24(10), 8784; https://doi.org/10.3390/ijms24108784 - 15 May 2023

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Abstract

During development, the heart is the first organ to form and function [...] Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardiac Development and Disease)

Research

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25 pages, 3862 KiB

Open AccessArticle

SMC5 Plays Independent Roles in Congenital Heart Disease and Neurodevelopmental Disability

by Matthew P. O’Brien, Marina V. Pryzhkova, Evelyn M. R. Lake, Francesca Mandino, Xilin Shen, Ruchika Karnik, Alisa Atkins, Michelle J. Xu, Weizhen Ji, Monica Konstantino, Martina Brueckner, Laura R. Ment, Mustafa K. Khokha and Philip W. Jordan

Int. J. Mol. Sci. 2024, 25(1), 430; https://doi.org/10.3390/ijms25010430 - 28 Dec 2023

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Abstract

Up to 50% of patients with severe congenital heart disease (CHD) develop life-altering neurodevelopmental disability (NDD). It has been presumed that NDD arises in CHD cases because of hypoxia before, during, or after cardiac surgery. Recent studies detected an enrichment in de novo [...] Read more.

Up to 50% of patients with severe congenital heart disease (CHD) develop life-altering neurodevelopmental disability (NDD). It has been presumed that NDD arises in CHD cases because of hypoxia before, during, or after cardiac surgery. Recent studies detected an enrichment in de novo mutations in CHD and NDD, as well as significant overlap between CHD and NDD candidate genes. However, there is limited evidence demonstrating that genes causing CHD can produce NDD independent of hypoxia. A patient with hypoplastic left heart syndrome and gross motor delay presented with a de novo mutation in SMC5. Modeling mutation of smc5 in Xenopus tropicalis embryos resulted in reduced heart size, decreased brain length, and disrupted pax6 patterning. To evaluate the cardiac development, we induced the conditional knockout (cKO) of Smc5 in mouse cardiomyocytes, which led to the depletion of mature cardiomyocytes and abnormal contractility. To test a role for Smc5 specifically in the brain, we induced cKO in the mouse central nervous system, which resulted in decreased brain volume, and diminished connectivity between areas related to motor function but did not affect vascular or brain ventricular volume. We propose that genetic factors, rather than hypoxia alone, can contribute when NDD and CHD cases occur concurrently. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardiac Development and Disease)

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13 pages, 6192 KiB

Open AccessArticle

A Two-Step Transcriptome Analysis of the Human Heart Reveals Broad and Disease-Responsive Expression of Ectopic Olfactory Receptors

by Sadia Ashraf, O. Howard Frazier, Sylvia Carranza, David D. McPherson, Heinrich Taegtmeyer and Romain Harmancey

Int. J. Mol. Sci. 2023, 24(18), 13709; https://doi.org/10.3390/ijms241813709 - 05 Sep 2023

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Abstract

G-protein-coupled receptors (GPCRs) are critical regulators of cardiac physiology and a key therapeutic target for the treatment of heart disease. Ectopic olfactory receptors (ORs) are GPCRs expressed in extra-nasal tissues which have recently emerged as new mediators in the metabolic control of cardiac [...] Read more.

G-protein-coupled receptors (GPCRs) are critical regulators of cardiac physiology and a key therapeutic target for the treatment of heart disease. Ectopic olfactory receptors (ORs) are GPCRs expressed in extra-nasal tissues which have recently emerged as new mediators in the metabolic control of cardiac function. The goals of this study were to profile OR gene expression in the human heart, to identify ORs dysregulated by heart failure caused by ischemic cardiomyopathy, and to provide evidence suggestive of a role for those altered ORs in the pathogenesis of heart failure. Left ventricular tissue from heart failure patients (n = 18) and non-failing heart samples (n = 4) were subjected to a two-step transcriptome analysis consisting of the quantification of 372 distinct OR transcripts on real-time PCR arrays and simultaneous determination of global cardiac gene expression by RNA sequencing. This strategy led to the identification of >160 ORs expressed in the human heart, including 38 receptors differentially regulated with heart failure. Co-expression analyses predicted the involvement of dysregulated ORs in the alteration of mitochondrial function, extracellular matrix remodeling, and inflammation. We provide this dataset as a resource for investigating roles of ORs in the human heart, with the hope that it will assist in the identification of new therapeutic targets for the treatment of heart failure. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardiac Development and Disease)

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17 pages, 8567 KiB

Open AccessArticle

FTY720-P, a Biased S1PR Ligand, Increases Mitochondrial Function through STAT3 Activation in Cardiac Cells

by Juan Pablo Muñoz, Paula Sànchez-Fernàndez-de-Landa, Elena María Goretti Diarte-Añazco, Antonio Zorzano, Francisco Blanco-Vaca and Josep Julve

Int. J. Mol. Sci. 2023, 24(8), 7374; https://doi.org/10.3390/ijms24087374 - 17 Apr 2023

Cited by 2 | Viewed by 1559

Abstract

FTY720 is an FDA-approved sphingosine derivative drug for the treatment of multiple sclerosis. This compound blocks lymphocyte egress from lymphoid organs and autoimmunity through sphingosine 1-phosphate (S1P) receptor blockage. Drug repurposing of FTY720 has revealed improvements in glucose metabolism and metabolic diseases. Studies [...] Read more.

FTY720 is an FDA-approved sphingosine derivative drug for the treatment of multiple sclerosis. This compound blocks lymphocyte egress from lymphoid organs and autoimmunity through sphingosine 1-phosphate (S1P) receptor blockage. Drug repurposing of FTY720 has revealed improvements in glucose metabolism and metabolic diseases. Studies also demonstrate that preconditioning with this compound preserves the ATP levels during cardiac ischemia in rats. The molecular mechanisms by which FTY720 promotes metabolism are not well understood. Here, we demonstrate that nanomolar concentrations of the phosphorylated form of FTY720 (FTY720-P), the active ligand of S1P receptor (S1PR), activates mitochondrial respiration and the mitochondrial ATP production rate in AC16 human cardiomyocyte cells. Additionally, FTY720-P increases the number of mitochondrial nucleoids, promotes mitochondrial morphology alterations, and induces activation of STAT3, a transcription factor that promotes mitochondrial function. Notably, the effect of FTY720-P on mitochondrial function was suppressed in the presence of a STAT3 inhibitor. In summary, our results suggest that FTY720 promotes the activation of mitochondrial function, in part, through a STAT3 action. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardiac Development and Disease)

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14 pages, 2193 KiB

Open AccessArticle

An Adjuvant Stem Cell Patch with Coronary Artery Bypass Graft Surgery Improves Diastolic Recovery in Porcine Hibernating Myocardium

by Rishav Aggarwal, Koray N. Potel, Annie Shao, Simon W. So, Cory Swingen, Christina P. Reyes, Rebecca Rose, Christin Wright, Laura L. Hocum Stone, Edward O. McFalls, Tammy A. Butterick and Rosemary F. Kelly

Int. J. Mol. Sci. 2023, 24(6), 5475; https://doi.org/10.3390/ijms24065475 - 13 Mar 2023

Cited by 2 | Viewed by 1511

Abstract

Diastolic dysfunction persists despite coronary artery bypass graft surgery (CABG) in patients with hibernating myocardium (HIB). We studied whether the adjunctive use of a mesenchymal stem cells (MSCs) patch during CABG improves diastolic function by reducing inflammation and fibrosis. HIB was induced in [...] Read more.

Diastolic dysfunction persists despite coronary artery bypass graft surgery (CABG) in patients with hibernating myocardium (HIB). We studied whether the adjunctive use of a mesenchymal stem cells (MSCs) patch during CABG improves diastolic function by reducing inflammation and fibrosis. HIB was induced in juvenile swine by placing a constrictor on the left anterior descending (LAD) artery, causing myocardial ischemia without infarction. At 12 weeks, CABG was performed using the left-internal-mammary-artery (LIMA)-to-LAD graft with or without placement of an epicardial vicryl patch embedded with MSCs, followed by four weeks of recovery. The animals underwent cardiac magnetic resonance imaging (MRI) prior to sacrifice, and tissue from septal and LAD regions were collected to assess for fibrosis and analyze mitochondrial and nuclear isolates. During low-dose dobutamine infusion, diastolic function was significantly reduced in HIB compared to the control, with significant improvement after CABG + MSC treatment. In HIB, we observed increased inflammation and fibrosis without transmural scarring, along with decreased peroxisome proliferator-activated receptor-gamma coactivator (PGC1α), which could be a possible mechanism underlying diastolic dysfunction. Improvement in PGC1α and diastolic function was noted with revascularization and MSCs, along with decreased inflammatory signaling and fibrosis. These findings suggest that adjuvant cell-based therapy during CABG may recover diastolic function by reducing oxidant stress–inflammatory signaling and myofibroblast presence in the myocardial tissue. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardiac Development and Disease)

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20 pages, 5857 KiB

Open AccessArticle

Malonyl-CoA Accumulation as a Compensatory Cytoprotective Mechanism in Cardiac Cells in Response to 7-Ketocholesterol-Induced Growth Retardation

by Mei-Ling Cheng, Cheng-Hung Yang, Pei-Ting Wu, Yi-Chin Li, Hao-Wei Sun, Gigin Lin and Hung-Yao Ho

Int. J. Mol. Sci. 2023, 24(5), 4418; https://doi.org/10.3390/ijms24054418 - 23 Feb 2023

Cited by 3 | Viewed by 1785

Abstract

The major oxidized product of cholesterol, 7-Ketocholesterol (7KCh), causes cellular oxidative damage. In the present study, we investigated the physiological responses of cardiomyocytes to 7KCh. A 7KCh treatment inhibited the growth of cardiac cells and their mitochondrial oxygen consumption. It was accompanied by [...] Read more.

The major oxidized product of cholesterol, 7-Ketocholesterol (7KCh), causes cellular oxidative damage. In the present study, we investigated the physiological responses of cardiomyocytes to 7KCh. A 7KCh treatment inhibited the growth of cardiac cells and their mitochondrial oxygen consumption. It was accompanied by a compensatory increase in mitochondrial mass and adaptive metabolic remodeling. The application of [U-¹³C] glucose labeling revealed an increased production of malonyl-CoA but a decreased formation of hydroxymethylglutaryl-coenzyme A (HMG-CoA) in the 7KCh-treated cells. The flux of the tricarboxylic acid (TCA) cycle decreased, while that of anaplerotic reaction increased, suggesting a net conversion of pyruvate to malonyl-CoA. The accumulation of malonyl-CoA inhibited the carnitine palmitoyltransferase-1 (CPT-1) activity, probably accounting for the 7-KCh-induced suppression of β-oxidation. We further examined the physiological roles of malonyl-CoA accumulation. Treatment with the inhibitor of malonyl-CoA decarboxylase, which increased the intracellular malonyl-CoA level, mitigated the growth inhibitory effect of 7KCh, whereas the treatment with the inhibitor of acetyl-CoA carboxylase, which reduced malonyl-CoA content, aggravated such a growth inhibitory effect. Knockout of malonyl-CoA decarboxylase gene (Mlycd^−/−) alleviated the growth inhibitory effect of 7KCh. It was accompanied by improvement of the mitochondrial functions. These findings suggest that the formation of malonyl-CoA may represent a compensatory cytoprotective mechanism to sustain the growth of 7KCh-treated cells. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardiac Development and Disease)

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12 pages, 1876 KiB

Open AccessArticle

Untargeted Metabolomics Identifies Potential Hypertrophic Cardiomyopathy Biomarkers in Carriers of MYBPC3 Founder Variants

by Mark Jansen, Maike Schuldt, Beau O. van Driel, Amand F. Schmidt, Imke Christiaans, Saskia N. van der Crabben, Yvonne M. Hoedemaekers, Dennis Dooijes, Jan D. H. Jongbloed, Ludolf G. Boven, Ronald H. Lekanne Deprez, Arthur A. M. Wilde, Judith J. M. Jans, Jolanda van der Velden, Rudolf A. de Boer, J. Peter van Tintelen, Folkert W. Asselbergs and Annette F. Baas

Int. J. Mol. Sci. 2023, 24(4), 4031; https://doi.org/10.3390/ijms24044031 - 17 Feb 2023

Cited by 3 | Viewed by 1942

Abstract

Hypertrophic cardiomyopathy (HCM) is the most prevalent monogenic heart disease, commonly caused by pathogenic MYBPC3 variants, and a significant cause of sudden cardiac death. Severity is highly variable, with incomplete penetrance among genotype-positive family members. Previous studies demonstrated metabolic changes in HCM. We [...] Read more.

Hypertrophic cardiomyopathy (HCM) is the most prevalent monogenic heart disease, commonly caused by pathogenic MYBPC3 variants, and a significant cause of sudden cardiac death. Severity is highly variable, with incomplete penetrance among genotype-positive family members. Previous studies demonstrated metabolic changes in HCM. We aimed to identify metabolite profiles associated with disease severity in carriers of MYBPC3 founder variants using direct-infusion high-resolution mass spectrometry in plasma of 30 carriers with a severe phenotype (maximum wall thickness ≥20 mm, septal reduction therapy, congestive heart failure, left ventricular ejection fraction <50%, or malignant ventricular arrhythmia) and 30 age- and sex-matched carriers with no or a mild phenotype. Of the top 25 mass spectrometry peaks selected by sparse partial least squares discriminant analysis, XGBoost gradient boosted trees, and Lasso logistic regression (42 total), 36 associated with severe HCM at a p < 0.05, 20 at p < 0.01, and 3 at p < 0.001. These peaks could be clustered to several metabolic pathways, including acylcarnitine, histidine, lysine, purine and steroid hormone metabolism, and proteolysis. In conclusion, this exploratory case-control study identified metabolites associated with severe phenotypes in MYBPC3 founder variant carriers. Future studies should assess whether these biomarkers contribute to HCM pathogenesis and evaluate their contribution to risk stratification. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardiac Development and Disease)

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10 pages, 1948 KiB

Open AccessArticle

Mechanisms for the α-Adrenoceptor-Mediated Positive Inotropy in Mouse Ventricular Myocardium: Enhancing Effect of Action Potential Prolongation

by Shogo Hamaguchi, Ikue Morinou, Yuko Shiseki, Ayako Mikami, Maika Seki, Iyuki Namekata and Hikaru Tanaka

Int. J. Mol. Sci. 2023, 24(4), 3926; https://doi.org/10.3390/ijms24043926 - 15 Feb 2023

Cited by 1 | Viewed by 1102

Abstract

Mechanisms for the α-adrenoceptor-mediated positive inotropy in neonatal mouse ventricular myocardium were studied with isolated myocardial preparations. The phenylephrine-induced positive inotropy was suppressed by prazosin, nifedipine, and chelerythrine, a protein kinase C inhibitor, but not by SEA0400, a selective Na⁺/Ca²⁺ [...] Read more.

Mechanisms for the α-adrenoceptor-mediated positive inotropy in neonatal mouse ventricular myocardium were studied with isolated myocardial preparations. The phenylephrine-induced positive inotropy was suppressed by prazosin, nifedipine, and chelerythrine, a protein kinase C inhibitor, but not by SEA0400, a selective Na⁺/Ca²⁺ exchanger inhibitor. Phenylephrine increased the L-type Ca²⁺ channel current and prolonged the action potential duration, while the voltage-dependent K⁺ channel current was not influenced. In the presence of cromakalim, an ATP-sensitive K⁺ channel opener, the phenylephrine-induced prolongation of action potential duration, as well as the positive inotropy, were smaller than in the absence of cromakalim. These results suggest that the α-adrenoceptor-mediated positive inotropy is mediated by an increase in Ca²⁺ influx through the L-type Ca²⁺ channel, and the concomitant increase in action potential duration acts as an enhancing factor. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardiac Development and Disease)

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15 pages, 4147 KiB

Open AccessArticle

Deep Paleoproteotyping and Microtomography Revealed No Heart Defect nor Traces of Embalming in the Cardiac Relics of Blessed Pauline Jaricot

by Virginie Bourdin, Philippe Charlier, Stéphane Crevat, Lotfi Slimani, Catherine Chaussain, Mélodie Kielbasa, Olivier Pible and Jean Armengaud

Int. J. Mol. Sci. 2023, 24(3), 3011; https://doi.org/10.3390/ijms24033011 - 03 Feb 2023

Cited by 6 | Viewed by 4928

Abstract

Scientific examination of the heart of Blessed Pauline Jaricot—a French missionary figure—was carried out in 2022. As tandem mass spectrometry proteotyping has proven to be valuable to obtain the broad taxonomic repertoire of a given sample without any a priori information, we aimed [...] Read more.

Scientific examination of the heart of Blessed Pauline Jaricot—a French missionary figure—was carried out in 2022. As tandem mass spectrometry proteotyping has proven to be valuable to obtain the broad taxonomic repertoire of a given sample without any a priori information, we aimed at exploring the conditions of preservation of the relics and possible conditions of death. Metaproteomics and high-resolution microtomography imaging approaches were combined. A dataset comprising 6731 high-resolution MS/MS spectra was acquired and 968 of these spectra could be assigned to specific peptidic biomolecules. Based on the taxonomical information encompassed by the identified peptide sequences, 5 phyla were identified amongst eukaryota (94% of the biomass): Ascomycota (55%), with the species Aspergillus versicolor, Trichophyton mentagrophytes and Aspergillus glaucus, corresponding to expected cadaverous fungal flora; Chordata (42%), represented by a unique species, Homo sapiens; Streptophyta (3%); and Arthropoda (traces). Bacteria (6% of the biomass) were poorly represented. No trace of embalming substance could be retrieved, nor any pathogens. Imaging evidenced no heart defect nor embalming traces. No evidence that was inconsistent with natural and spontaneous conservation could be retrieved. This study prefigures the power of modern molecular techniques such as paleoproteotyping coupled to microtomography to gain insight into historical relics. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardiac Development and Disease)

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15 pages, 1539 KiB

Open AccessArticle

by Francesca Di Lorenzo, Enrica Marchionni, Valentina Ferradini, Andrea Latini, Laura Pezzoli, Annamaria Martino, Fabiana Romeo, Annamaria Iorio, Stefano Bianchi, Maria Iascone, Leonardo Calò, Giuseppe Novelli, Ruggiero Mango and Federica Sangiuolo

Int. J. Mol. Sci. 2023, 24(3), 2490; https://doi.org/10.3390/ijms24032490 - 27 Jan 2023

Cited by 8 | Viewed by 1942

Abstract

Variants in desmoplakin gene (DSP MIM *125647) have been usually associated with Arrhythmogenic Cardiomyopathy (ACM), or Dilated Cardiomyopathy (DCM) inherited in an autosomal dominant manner. A cohort of 18 probands, characterized as heterozygotes for DSP variants by a target Next Generation Sequencing [...] Read more.

Variants in desmoplakin gene (DSP MIM *125647) have been usually associated with Arrhythmogenic Cardiomyopathy (ACM), or Dilated Cardiomyopathy (DCM) inherited in an autosomal dominant manner. A cohort of 18 probands, characterized as heterozygotes for DSP variants by a target Next Generation Sequencing (NGS) cardiomyopathy panel, was analyzed. Cardiological, genetic data, and imaging features were retrospectively collected. A total of 16 DSP heterozygous pathogenic or likely pathogenic variants were identified, 75% (n = 12) truncating variants, n = 2 missense variants, n = 1 splicing variant, and n = 1 duplication variant. The mean age at diagnosis was 40.61 years (IQR 31–47.25), 61% of patients being asymptomatic (n = 11, New York Heart Association (NYHA) class I) and 39% mildly symptomatic (n = 7, NYHA class II). Notably, 39% of patients (n = 7) presented with a clinical history of presumed myocarditis episodes, characterized by chest pain, myocardial enzyme release, 12-lead electrocardiogram abnormalities with normal coronary arteries, which were recurrent in 57% of cases (n = 4). About half of the patients (55%, n = 10) presented with a varied degree of left ventricular enlargement (LVE), four showing biventricular involvement. Eleven patients (61%) underwent implantable cardioverter defibrillator (ICD) implantation, with a mean age of 46.81 years (IQR 36.00–64.00). Cardiac magnetic resonance imaging (CMRI) identified in all 18 patients a delayed enhancement (DE) area consistent with left ventricular (LV) myocardial fibrosis, with a larger localization and extent in patients presenting with recurrent episodes of myocardial injury. These clinical and genetic data confirm that DSP-related cardiomyopathy may represent a distinct clinical entity characterized by a high arrhythmic burden, variable degrees of LVE, Late Gadolinium Enhancement (LGE) with subepicardial distribution and episodes of myocarditis-like picture. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardiac Development and Disease)

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15 pages, 2445 KiB

Open AccessArticle

Cardiac Differentiation Promotes Focal Adhesions Assembly through Vinculin Recruitment

by Flavia Carton, Simona Casarella, Dalila Di Francesco, Emma Zanella, Annarita D'urso, Luca Di Nunno, Luca Fusaro, Diego Cotella, Maria Prat, Antonia Follenzi and Francesca Boccafoschi

Int. J. Mol. Sci. 2023, 24(3), 2444; https://doi.org/10.3390/ijms24032444 - 26 Jan 2023

Cited by 3 | Viewed by 2241

Abstract

Cells of the cardiovascular system are physiologically exposed to a variety of mechanical forces fundamental for both cardiac development and functions. In this context, forces generated by actomyosin networks and those transmitted through focal adhesion (FA) complexes represent the key regulators of cellular [...] Read more.

Cells of the cardiovascular system are physiologically exposed to a variety of mechanical forces fundamental for both cardiac development and functions. In this context, forces generated by actomyosin networks and those transmitted through focal adhesion (FA) complexes represent the key regulators of cellular behaviors in terms of cytoskeleton dynamism, cell adhesion, migration, differentiation, and tissue organization. In this study, we investigated the involvement of FAs on cardiomyocyte differentiation. In particular, vinculin and focal adhesion kinase (FAK) family, which are known to be involved in cardiac differentiation, were studied. Results revealed that differentiation conditions induce an upregulation of both FAK-Tyr397 and vinculin, resulting also in the translocation to the cell membrane. Moreover, the role of mechanical stress in contractile phenotype expression was investigated by applying a uniaxial mechanical stretching (5% substrate deformation, 1 Hz frequency). Morphological evaluation revealed that the cell shape showed a spindle shape and reoriented following the stretching direction. Substrate deformation resulted also in modification of the length and the number of vinculin-positive FAs. We can, therefore, suggest that mechanotransductive pathways, activated through FAs, are highly involved in cardiomyocyte differentiation, thus confirming their role during cytoskeleton rearrangement and cardiac myofilament maturation. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardiac Development and Disease)

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17 pages, 3856 KiB

Open AccessArticle

CCBE1 Is Essential for Epicardial Function during Myocardium Development

by Fernando Bonet, Sabrina Brito Añez, José Manuel Inácio, Matthias E. Futschik and José Antonio Belo

Int. J. Mol. Sci. 2022, 23(20), 12642; https://doi.org/10.3390/ijms232012642 - 20 Oct 2022

Cited by 1 | Viewed by 1880

Abstract

The epicardium is a single cell layer of mesothelial cells that plays a critical role during heart development contributing to different cardiac cell types of the developing heart through epithelial-to-mesenchymal transition (EMT). Moreover, the epicardium is a source of secreted growth factors that [...] Read more.

The epicardium is a single cell layer of mesothelial cells that plays a critical role during heart development contributing to different cardiac cell types of the developing heart through epithelial-to-mesenchymal transition (EMT). Moreover, the epicardium is a source of secreted growth factors that promote myocardial growth. CCBE1 is a secreted extracellular matrix protein expressed by epicardial cells that is required for the formation of the primitive coronary plexus. However, the role of CCBE1 during epicardial development was still unknown. Here, using a Ccbe1 knockout (KO) mouse model, we observed that loss of CCBE1 leads to congenital heart defects including thinner and hyper-trabeculated ventricular myocardium. In addition, Ccbe1 mutant hearts displayed reduced proliferation of cardiomyocyte and epicardial cells. Epicardial outgrowth culture assay to assess epicardial-derived cells (EPDC) migration showed reduced invasion of the collagen gel by EPDCs in Ccbe1 KO epicardial explants. Ccbe1 KO hearts also displayed fewer nonmyocyte/nonendothelial cells intramyocardially with a reduced proliferation rate. Additionally, RNA-seq data and experimental validation by qRT-PCR showed a marked deregulation of EMT-related genes in developing Ccbe1 mutant hearts. Together, these findings indicate that the myocardium defects in Ccbe1 KO mice arise from disruption of epicardial development and function. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardiac Development and Disease)

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Review

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24 pages, 3963 KiB

Open AccessReview

Maternal Pre-Existing Diabetes: A Non-Inherited Risk Factor for Congenital Cardiopathies

by Stéphanie Ibrahim, Bénédicte Gaborit, Marien Lenoir, Gwenaelle Collod-Beroud and Sonia Stefanovic

Int. J. Mol. Sci. 2023, 24(22), 16258; https://doi.org/10.3390/ijms242216258 - 13 Nov 2023

Cited by 3 | Viewed by 1124

Abstract

Congenital heart defects (CHDs) are the most common form of birth defects in humans. They occur in 9 out of 1000 live births and are defined as structural abnormalities of the heart. Understanding CHDs is difficult due to the heterogeneity of the disease [...] Read more.

Congenital heart defects (CHDs) are the most common form of birth defects in humans. They occur in 9 out of 1000 live births and are defined as structural abnormalities of the heart. Understanding CHDs is difficult due to the heterogeneity of the disease and its multifactorial etiology. Advances in genomic sequencing have made it possible to identify the genetic factors involved in CHDs. However, genetic origins have only been found in a minority of CHD cases, suggesting the contribution of non-inherited (environmental) risk factors to the etiology of CHDs. Maternal pregestational diabetes is associated with a three- to five-fold increased risk of congenital cardiopathies, but the underlying molecular mechanisms are incompletely understood. According to current hypotheses, hyperglycemia is the main teratogenic agent in diabetic pregnancies. It is thought to induce cell damage, directly through genetic and epigenetic dysregulations and/or indirectly through production of reactive oxygen species (ROS). The purpose of this review is to summarize key findings on the molecular mechanisms altered in cardiac development during exposure to hyperglycemic conditions in utero. It also presents the various in vivo and in vitro techniques used to experimentally model pregestational diabetes. Finally, new approaches are suggested to broaden our understanding of the subject and develop new prevention strategies. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardiac Development and Disease)

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12 pages, 1907 KiB

Open AccessReview

Emerging Roles of Phospholipase C Beta Isozymes as Potential Biomarkers in Cardiac Disorders

by Antonietta Fazio, Camilla Evangelisti, Alessandra Cappellini, Sara Mongiorgi, Foteini-Dionysia Koufi, Irene Neri, Maria Vittoria Marvi, Michele Russo, Alessandra Ghigo, Lucia Manzoli, Roberta Fiume and Stefano Ratti

Int. J. Mol. Sci. 2023, 24(17), 13096; https://doi.org/10.3390/ijms241713096 - 23 Aug 2023

Viewed by 1154

Abstract

Phospholipase C (PLC) enzymes represent crucial participants in the plasma membrane of mammalian cells, including the cardiac sarcolemmal (SL) membrane of cardiomyocytes. They are responsible for the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P₂) into 1,2-diacylglycerol (DAG) and inositol (1,4,5) trisphosphate (Ins(1,4,5)P₃ [...] Read more.

Phospholipase C (PLC) enzymes represent crucial participants in the plasma membrane of mammalian cells, including the cardiac sarcolemmal (SL) membrane of cardiomyocytes. They are responsible for the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P₂) into 1,2-diacylglycerol (DAG) and inositol (1,4,5) trisphosphate (Ins(1,4,5)P₃), both essential lipid mediators. These second messengers regulate the intracellular calcium (Ca²⁺) concentration, which activates signal transduction cascades involved in the regulation of cardiomyocyte activity. Of note, emerging evidence suggests that changes in cardiomyocytes’ phospholipid profiles are associated with an increased occurrence of cardiovascular diseases, but the underlying mechanisms are still poorly understood. This review aims to provide a comprehensive overview of the significant impact of PLC on the cardiovascular system, encompassing both physiological and pathological conditions. Specifically, it focuses on the relevance of PLCβ isoforms as potential cardiac biomarkers, due to their implications for pathological disorders, such as cardiac hypertrophy, diabetic cardiomyopathy, and myocardial ischemia/reperfusion injury. Gaining a deeper understanding of the mechanisms underlying PLCβ activation and regulation is crucial for unraveling the complex signaling networks involved in healthy and diseased myocardium. Ultimately, this knowledge holds significant promise for advancing the development of potential therapeutic strategies that can effectively target and address cardiac disorders by focusing on the PLCβ subfamily. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardiac Development and Disease)

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16 pages, 1620 KiB

Open AccessReview

RNA-Binding Proteins as Critical Post-Transcriptional Regulators of Cardiac Regeneration

by De-Li Shi

Int. J. Mol. Sci. 2023, 24(15), 12004; https://doi.org/10.3390/ijms241512004 - 26 Jul 2023

Cited by 4 | Viewed by 2120

Abstract

Myocardial injury causes death to cardiomyocytes and leads to heart failure. The adult mammalian heart has very limited regenerative capacity. However, the heart from early postnatal mammals and from adult lower vertebrates can fully regenerate after apical resection or myocardial infarction. Thus, it [...] Read more.

Myocardial injury causes death to cardiomyocytes and leads to heart failure. The adult mammalian heart has very limited regenerative capacity. However, the heart from early postnatal mammals and from adult lower vertebrates can fully regenerate after apical resection or myocardial infarction. Thus, it is of particular interest to decipher the mechanism underlying cardiac regeneration that preserves heart structure and function. RNA-binding proteins, as key regulators of post-transcriptional gene expression to coordinate cell differentiation and maintain tissue homeostasis, display dynamic expression in fetal and adult hearts. Accumulating evidence has demonstrated their importance for the survival and proliferation of cardiomyocytes following neonatal and postnatal cardiac injury. Functional studies suggest that RNA-binding proteins relay damage-stimulated cell extrinsic or intrinsic signals to regulate heart regenerative capacity by reprogramming multiple molecular and cellular processes, such as global protein synthesis, metabolic changes, hypertrophic growth, and cellular plasticity. Since manipulating the activity of RNA-binding proteins can improve the formation of new cardiomyocytes and extend the window of the cardiac regenerative capacity in mammals, they are potential targets of therapeutic interventions for cardiovascular disease. This review discusses our evolving understanding of RNA-binding proteins in regulating cardiac repair and regeneration, with the aim to identify important open questions that merit further investigations. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardiac Development and Disease)

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17 pages, 2587 KiB

Open AccessReview

LncRNAs and CircRNAs in Endoplasmic Reticulum Stress: A Promising Target for Cardiovascular Disease?

by Francisco José Martinez-Amaro, Carlos Garcia-Padilla, Diego Franco and Houria Daimi

Int. J. Mol. Sci. 2023, 24(12), 9888; https://doi.org/10.3390/ijms24129888 - 08 Jun 2023

Cited by 3 | Viewed by 1425

Abstract

The endoplasmic reticulum (ER) is a principal subcellular organelle responsible for protein quality control in the secretory pathway, preventing protein misfolding and aggregation. Failure of protein quality control in the ER triggers several molecular mechanisms such as ER-associated degradation (ERAD), the unfolded protein [...] Read more.

The endoplasmic reticulum (ER) is a principal subcellular organelle responsible for protein quality control in the secretory pathway, preventing protein misfolding and aggregation. Failure of protein quality control in the ER triggers several molecular mechanisms such as ER-associated degradation (ERAD), the unfolded protein response (UPR) or reticulophagy, which are activated upon ER stress (ERS) to re-establish protein homeostasis by transcriptionally and translationally regulated complex signalling pathways. However, maintenance over time of ERS leads to apoptosis if such stress cannot be alleviated. The presence of abnormal protein aggregates results in loss of cardiomyocyte protein homeostasis, which in turn results in several cardiovascular diseases such as dilated cardiomyopathy (DCM) or myocardial infarction (MI). The influence of a non-coding genome in the maintenance of proper cardiomyocyte homeostasis has been widely proven. To date, the impact of microRNAs in molecular mechanisms orchestrating ER stress response has been widely described. However, the role of long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) is just beginning to be addressed given the potential role of these RNA classes as therapeutic molecules. Here, we provide a current state-of-the-art review of the roles of distinct lncRNAs and circRNAs in the modulation of ERS and UPR and their impact in cardiovascular diseases. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardiac Development and Disease)

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13 pages, 962 KiB

Open AccessReview

Atrial Natriuretic Peptides as a Bridge between Atrial Fibrillation, Heart Failure, and Amyloidosis of the Atria

by Farzad Rahbar Kouibaran, Mario Sabatino, Chiara Barozzi and Igor Diemberger

Int. J. Mol. Sci. 2023, 24(7), 6470; https://doi.org/10.3390/ijms24076470 - 30 Mar 2023

Cited by 5 | Viewed by 1808

Abstract

ANP is mainly synthesized by the atria, and upon excretion, it serves two primary purposes: vasodilation and increasing the renal excretion of sodium and water. The understanding of ANP’s role in cardiac systems has improved considerably in recent decades. This review focuses on [...] Read more.

ANP is mainly synthesized by the atria, and upon excretion, it serves two primary purposes: vasodilation and increasing the renal excretion of sodium and water. The understanding of ANP’s role in cardiac systems has improved considerably in recent decades. This review focuses on several studies demonstrating the importance of analyzing the regulations between the endocrine and mechanical function of the heart and emphasizes the effect of ANP, as the primary hormone of the atria, on atrial fibrillation (AF) and related diseases. The review first discusses the available data on the diagnostic and therapeutic applications of ANP and then explains effect of ANP on heart failure (HF) and atrial fibrillation (AF) and vice versa, where tracking ANP levels could lead to understanding the pathophysiological mechanisms operating in these diseases. Second, it focuses on conventional treatments for AF, such as cardioversion and catheter ablation, and their effects on cardiac endocrine and mechanical function. Finally, it provides a point of view about the delayed recovery of cardiac mechanical and endocrine function after cardioversion, which can contribute to the occurrence of acute heart failure, and the potential impact of restoration of the sinus rhythm by extensive ablation or surgery in losing ANP-producing sites. Overall, ANP plays a key role in heart failure through its effects on vasodilation and natriuresis, leading to a decrease in the activity of the renin-angiotensin-aldosterone system, but it is crucial to understand the intimate role of ANP in HF and AF to improve their diagnosis and personalizing the patients’ treatment. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardiac Development and Disease)

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15 pages, 1133 KiB

Open AccessReview

Renal and Cardiovascular Metabolic Impact Caused by Ketogenesis of the SGLT2 Inhibitors

by Ariana P. Vargas-Delgado, Estefania Arteaga Herrera, Cesar Tumbaco Mite, Patricia Delgado Cedeno, Maria Cristina Van Loon and Juan J. Badimon

Int. J. Mol. Sci. 2023, 24(4), 4144; https://doi.org/10.3390/ijms24044144 - 18 Feb 2023

Cited by 5 | Viewed by 2576

Abstract

Sodium–glucose cotransporter type 2 inhibitors (SGLT2i) are glycosuric drugs that were originally developed for the treatment of type 2 diabetes mellitus (T2DM). There is a hypothesis that SGLT2i are drugs that are capable of increasing ketone bodies and free fatty acids. The idea [...] Read more.

Sodium–glucose cotransporter type 2 inhibitors (SGLT2i) are glycosuric drugs that were originally developed for the treatment of type 2 diabetes mellitus (T2DM). There is a hypothesis that SGLT2i are drugs that are capable of increasing ketone bodies and free fatty acids. The idea is that they could serve as the necessary fuel, instead of glucose, for the purposes of cardiac muscle requirements and could explain antihypertensive effects, which are independent of renal function. The adult heart, under normal conditions, consumes around 60% to 90% of the cardiac energy that is derived from the oxidation of free fatty acids. In addition, a small proportion also comes from other available substrates. In order to meet energy demands with respect to achieving adequate cardiac function, the heart is known to possess metabolic flexibility. This allows it to switch between different available substrates in order to obtain the energy molecule adenosine triphosphate (ATP), thereby rendering it highly adaptive. It must be noted that oxidative phosphorylation in aerobic organisms is the main source of ATP, which is a result of reduced cofactors. These cofactors include nicotine adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2), which are the result of electron transfer and are used as the enzymatic cofactors that are involved in the respiratory chain. When there is an excessive increase in energy nutrients—such as glucose and fatty acids—which occur in the absence of a parallel increase in demand, a state of nutrient surplus (which is better known as an excess in supply) is created. The use of SGLT2i at the renal level has also been shown to generate beneficial metabolic alterations, which are obtained by reducing the glucotoxicity that is induced by glycosuria. Together with the reduction in perivisceral fat in various organs, such alterations also lead to the use of free fatty acids in the initial stages of the affected heart. Subsequently, this results in an increase in production with respect to ketoacids, which are a more available energy fuel at the cellular level. In addition, even though their mechanism is not fully understood, their vast benefits render them of incredible importance for the purposes of further research. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardiac Development and Disease)

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21 pages, 722 KiB

Open AccessReview

Pharmacological Utility of PPAR Modulation for Angiogenesis in Cardiovascular Disease

by Nicole Wagner and Kay-Dietrich Wagner

Int. J. Mol. Sci. 2023, 24(3), 2345; https://doi.org/10.3390/ijms24032345 - 25 Jan 2023

Cited by 12 | Viewed by 2876

Abstract

Peroxisome proliferator activated receptors, including PPARα, PPARβ/δ, and PPARγ, are ligand-activated transcription factors belonging to the nuclear receptor superfamily. They play important roles in glucose and lipid metabolism and are also supposed to reduce inflammation and atherosclerosis. All PPARs are involved in angiogenesis, [...] Read more.

Peroxisome proliferator activated receptors, including PPARα, PPARβ/δ, and PPARγ, are ligand-activated transcription factors belonging to the nuclear receptor superfamily. They play important roles in glucose and lipid metabolism and are also supposed to reduce inflammation and atherosclerosis. All PPARs are involved in angiogenesis, a process critically involved in cardiovascular pathology. Synthetic specific agonists exist for all PPARs. PPARα agonists (fibrates) are used to treat dyslipidemia by decreasing triglyceride and increasing high-density lipoprotein (HDL) levels. PPARγ agonists (thiazolidinediones) are used to treat Type 2 diabetes mellitus by improving insulin sensitivity. PPARα/γ (dual) agonists are supposed to treat both pathological conditions at once. In contrast, PPARβ/δ agonists are not in clinical use. Although activators of PPARs were initially considered to have favorable effects on the risk factors for cardiovascular disease, their cardiovascular safety is controversial. Here, we discuss the implications of PPARs in vascular biology regarding cardiac pathology and focus on the outcomes of clinical studies evaluating their benefits in cardiovascular diseases. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardiac Development and Disease)

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20 pages, 1330 KiB

Open AccessReview

Monomeric C-Reactive Protein in Atherosclerotic Cardiovascular Disease: Advances and Perspectives

by Ivan Melnikov, Sergey Kozlov, Olga Saburova, Yuliya Avtaeva, Konstantin Guria and Zufar Gabbasov

Int. J. Mol. Sci. 2023, 24(3), 2079; https://doi.org/10.3390/ijms24032079 - 20 Jan 2023

Cited by 8 | Viewed by 4949

Abstract

This review aimed to trace the inflammatory pathway from the NLRP3 inflammasome to monomeric C-reactive protein (mCRP) in atherosclerotic cardiovascular disease. CRP is the final product of the interleukin (IL)-1β/IL-6/CRP axis. Its monomeric form can be produced at sites of local inflammation through [...] Read more.

This review aimed to trace the inflammatory pathway from the NLRP3 inflammasome to monomeric C-reactive protein (mCRP) in atherosclerotic cardiovascular disease. CRP is the final product of the interleukin (IL)-1β/IL-6/CRP axis. Its monomeric form can be produced at sites of local inflammation through the dissociation of pentameric CRP and, to some extent, local synthesis. mCRP has a distinct proinflammatory profile. In vitro and animal-model studies have suggested a role for mCRP in: platelet activation, adhesion, and aggregation; endothelial activation; leukocyte recruitment and polarization; foam-cell formation; and neovascularization. mCRP has been shown to deposit in atherosclerotic plaques and damaged tissues. In recent years, the first published papers have reported the development and application of mCRP assays. Principally, these studies demonstrated the feasibility of measuring mCRP levels. With recent advances in detection techniques and the introduction of first assays, mCRP-level measurement should become more accessible and widely used. To date, anti-inflammatory therapy in atherosclerosis has targeted the NLRP3 inflammasome and upstream links of the IL-1β/IL-6/CRP axis. Large clinical trials have provided sufficient evidence to support this strategy. However, few compounds target CRP. Studies on these agents are limited to animal models or small clinical trials. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardiac Development and Disease)

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19 pages, 1634 KiB

Open AccessReview

Modified mRNA Therapeutics for Heart Diseases

by Ajit Magadum

Int. J. Mol. Sci. 2022, 23(24), 15514; https://doi.org/10.3390/ijms232415514 - 08 Dec 2022

Cited by 4 | Viewed by 3183

Abstract

Cardiovascular diseases (CVD) remain a substantial global health problem and the leading cause of death worldwide. Although many conventional small-molecule treatments are available to support the cardiac function of the patient with CVD, they are not effective as a cure. Among potential targets [...] Read more.

Cardiovascular diseases (CVD) remain a substantial global health problem and the leading cause of death worldwide. Although many conventional small-molecule treatments are available to support the cardiac function of the patient with CVD, they are not effective as a cure. Among potential targets for gene therapy are severe cardiac and peripheral ischemia, heart failure, vein graft failure, and some forms of dyslipidemias. In the last three decades, multiple gene therapy tools have been used for heart diseases caused by proteins, plasmids, adenovirus, and adeno-associated viruses (AAV), but these remain as unmet clinical needs. These gene therapy methods are ineffective due to poor and uncontrolled gene expression, low stability, immunogenicity, and transfection efficiency. The synthetic modified mRNA (modRNA) presents a novel gene therapy approach which provides a transient, stable, safe, non-immunogenic, controlled mRNA delivery to the heart tissue without any risk of genomic integration, and achieves a therapeutic effect in different organs, including the heart. The mRNA translation starts in minutes, and remains stable for 8–10 days (pulse-like kinetics). The pulse-like expression of modRNA in the heart induces cardiac repair, cardiomyocyte proliferation and survival, and inhibits cardiomyocyte apoptosis post-myocardial infarction (MI). Cell-specific (cardiomyocyte) modRNA translation developments established cell-specific modRNA therapeutics for heart diseases. With these laudable characteristics, combined with its expression kinetics in the heart, modRNA has become an attractive therapeutic for the treatment of CVD. This review discusses new developments in modRNA therapy for heart diseases. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardiac Development and Disease)

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