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Molecular Mechanisms and Pathophysiology of Myocardial Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 May 2024) | Viewed by 5935

Special Issue Editors


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Guest Editor
Department of Internal Medicine, University of Arizona College of Medicine–Phoenix, Phoenix, AZ 85004, USA
Interests: molecular and pathophysiologic mechanisms of cardiomyopathy; heart failure and concurrent complications
Special Issues, Collections and Topics in MDPI journals

E-Mail Website
Guest Editor
Department of Internal Medicine, University of Arizona College of Medicine – Phoenix, Phoenix, AZ 85004, USA
Interests: cardiovascular imaging; cardiomyopathy; thrombosis; heart failure; translational models
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Numerous advances have been made in cardiovascular medicine in recent years, though a complete understanding of the mechanisms and pathophysiology remain largely under-reported. Details at the molecular level of the myocardium and systemic molecular mechanisms are needed to improve the understanding of disease development, progression, and endstage characteristics (etiologies which include ischemic, toxic, genetic, etc.). The specialized muscle is important for cardiac contractility, ion exchange, systemic perfusion, coronary circulation, and pathological/compensatory remodeling (hypertrophic, dilated, arrhythmogenic or restrictive). Physiological changes from inflammation or infection, fluid dynamics (hypertension, volume overload, etc.), or concurrent diseases (comorbidities: diabetes mellitus, renal and liver dysfunction, atherosclerosis, sarcopenia/cachexia, COPD) also have profound outcomes on the myocardium. New insights may lead to discovery of potential biomarkers, targets for pharmacological intervention, and eventually preventative strategies for those at risk of cardiomyopathy and resulting heart failure.          

This Special Issue within International Journal of Molecular Sciences welcomes original research manuscripts from pre-clinical and clinical studies, review articles, and brief reports focusing on molecular mechanisms and pathophysiology associated with myocardial disease and heart failure.

Prof. Dr. Inna P. Gladysheva
Dr. Ryan D. Sullivan
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • myocardiac disease
  • cardiomyopathy
  • fibrosis
  • heart failure
  • comorbidity
  • molecular mechanisms
  • pathophysiology

Published Papers (4 papers)

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Research

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17 pages, 998 KiB  
Article
Cardiac-Specific Suppression of Valosin-Containing Protein Induces Progressive Heart Failure and Premature Mortality Correlating with Temporal Dysregulations in mTOR Complex 2 and Protein Phosphatase 1
by Xiaonan Sun, Xicong Tang and Hongyu Qiu
Int. J. Mol. Sci. 2024, 25(12), 6445; https://doi.org/10.3390/ijms25126445 - 11 Jun 2024
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Abstract
Valosin-containing protein (VCP), an ATPase-associated protein, is emerging as a crucial regulator in cardiac pathologies. However, the pivotal role of VCP in the heart under physiological conditions remains undetermined. In this study, we tested a hypothesis that sufficient VCP expression is required for [...] Read more.
Valosin-containing protein (VCP), an ATPase-associated protein, is emerging as a crucial regulator in cardiac pathologies. However, the pivotal role of VCP in the heart under physiological conditions remains undetermined. In this study, we tested a hypothesis that sufficient VCP expression is required for cardiac development and physiological cardiac function. Thus, we generated a cardiac-specific VCP knockout (KO) mouse model and assessed the consequences of VCP suppression on the heart through physiological and molecular studies at baseline. Our results reveal that homozygous KO mice are embryonically lethal, whereas heterozygous KO mice with a reduction in VCP by ~40% in the heart are viable at birth but progressively develop heart failure and succumb to mortality at the age of 10 to 12 months. The suppression of VCP induced a selective activation of the mammalian target of rapamycin complex 1 (mTORC1) but not mTORC2 at the early age of 12 weeks. The prolonged suppression of VCP increased the expression (by ~2 folds) and nuclear translocation (by >4 folds) of protein phosphatase 1 (PP1), a key mediator of protein dephosphorylation, accompanied by a remarked reduction (~80%) in AKTSer473 phosphorylation in VCP KO mouse hearts at a later age but not the early stage. These temporal molecular alterations were highly associated with the progressive decline in cardiac function. Overall, our findings shed light on the essential role of VCP in the heart under physiological conditions, providing new insights into molecular mechanisms in the development of heart failure. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Myocardial Disease)
19 pages, 3445 KiB  
Article
Cirrhotic Cardiomyopathy Following Bile Duct Ligation in Rats—A Matter of Time?
by Moritz Uhlig, Marc Hein, Moriz A. Habigt, René H. Tolba, Till Braunschweig, Marius J. Helmedag, Melissa Arici, Alexander Theißen, Axel Klinkenberg, Uwe Klinge and Mare Mechelinck
Int. J. Mol. Sci. 2023, 24(9), 8147; https://doi.org/10.3390/ijms24098147 - 2 May 2023
Cited by 3 | Viewed by 1865
Abstract
Cirrhotic patients often suffer from cirrhotic cardiomyopathy (CCM). Previous animal models of CCM were inconsistent concerning the time and mechanism of injury; thus, the temporal dynamics and cardiac vulnerability were studied in more detail. Rats underwent bile duct ligation (BDL) and a second [...] Read more.
Cirrhotic patients often suffer from cirrhotic cardiomyopathy (CCM). Previous animal models of CCM were inconsistent concerning the time and mechanism of injury; thus, the temporal dynamics and cardiac vulnerability were studied in more detail. Rats underwent bile duct ligation (BDL) and a second surgery 28 days later. Cardiac function was assessed by conductance catheter and echocardiography. Histology, gene expression, and serum parameters were analyzed. A chronotropic incompetence (Pd31 < 0.001) and impaired contractility at rest and a reduced contractile reserve (Pd31 = 0.03, Pdob-d31 < 0.001) were seen 31 days after BDL with increased creatine (Pd35, Pd42, and Pd56 < 0.05) and transaminases (Pd31 < 0.001). A total of 56 days after BDL, myocardial fibrosis was seen (Pd56 < 0.001) accompanied by macrophage infiltration (CD68: Pgroup < 0.001) and systemic inflammation (TNFα: Pgroup < 0.001, white blood cell count: Pgroup < 0.001). Myocardial expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) was increased after 31 (Pd31 < 0.001) and decreased after 42 (Pd42 < 0.001) and 56 days (Pd56 < 0.001). Caspase-3 expression was increased 31 and 56 days after BDL (Pd31 = 0.005; Pd56 = 0.005). Structural changes in the myocardium were seen after 8 weeks. After the second surgery (second hit), transient myocardial insufficiency with secondary organ dysfunction was seen, characterized by reduced contractility and contractile reserve. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Myocardial Disease)
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12 pages, 2254 KiB  
Article
Molecular Mechanisms Underlying the Progression of Aortic Valve Stenosis: Bioinformatic Analysis of Signal Pathways and Hub Genes
by Taiki Tojo and Minako Yamaoka-Tojo
Int. J. Mol. Sci. 2023, 24(9), 7964; https://doi.org/10.3390/ijms24097964 - 27 Apr 2023
Viewed by 1828
Abstract
The calcification of the aortic valve causes increased leaflet stiffness and leads to the development and progression of stenotic aortic valve disease. However, the molecular and cellular mechanisms underlying stenotic calcification remain poorly understood. Herein, we examined the gene expression associated with valve [...] Read more.
The calcification of the aortic valve causes increased leaflet stiffness and leads to the development and progression of stenotic aortic valve disease. However, the molecular and cellular mechanisms underlying stenotic calcification remain poorly understood. Herein, we examined the gene expression associated with valve calcification and the progression of calcific aortic valve stenosis. We downloaded two publicly available gene expression profiles (GSE83453 and GSE51472) from NCBI-Gene Expression Omnibus database for the combined analysis of samples from human aortic stenosis and normal aortic valve tissue. After identifying the differentially expressed genes (DEGs) using the GEO2R online tool, we performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. We also analyzed the protein–protein interactions (PPIs) of the DEGs using the NetworkAnalyst online tool. We identified 4603 upregulated and 6272 downregulated DEGs, which were enriched in the positive regulation of cell adhesion, leukocyte-mediated immunity, response to hormones, cytokine signaling in the immune system, lymphocyte activation, and growth hormone receptor signaling. PPI network analysis identified 10 hub genes: VCAM1, FHL2, RUNX1, TNFSF10, PLAU, SPOCK1, CD74, SIPA1L2, TRIB1, and CXCL12. Through bioinformatic analysis, we identified potential biomarkers and therapeutic targets for aortic stenosis, providing a theoretical basis for future studies. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Myocardial Disease)
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Review

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16 pages, 1960 KiB  
Review
Experimental Models to Study Endothelial to Mesenchymal Transition in Myocardial Fibrosis and Cardiovascular Diseases
by Mohammed Mimouni, Anne-Dominique Lajoix and Caroline Desmetz
Int. J. Mol. Sci. 2024, 25(1), 382; https://doi.org/10.3390/ijms25010382 - 27 Dec 2023
Viewed by 1181
Abstract
Fibrosis is a common feature of cardiovascular diseases and targets multiple organs, such as the heart and vessels. Endothelial to mesenchymal transition is a complex, vital process that occurs during embryonic formation and plays a crucial role in cardiac development. It is also [...] Read more.
Fibrosis is a common feature of cardiovascular diseases and targets multiple organs, such as the heart and vessels. Endothelial to mesenchymal transition is a complex, vital process that occurs during embryonic formation and plays a crucial role in cardiac development. It is also a fundamental process implicated in cardiac fibrosis and repair, but also in other organs. Indeed, in numerous cardiovascular diseases, the endothelial-to-mesenchymal transition has been shown to be involved in the generation of fibroblasts that are able to produce extracellular matrix proteins such as type I collagen. This massive deposition results in tissue stiffening and organ dysfunction. To advance our understanding of this process for the development of new specific diagnostic and therapeutic strategies, it is essential to develop relevant cellular and animal models of this process. In this review, our aim was to gain an in-depth insight into existing in vitro and in vivo models of endothelial to mesenchymal transition in cardiovascular diseases with a focus on cardiac fibrosis. We discuss important parameters impacting endothelial to mesenchymal transition, and we give perspectives for the development of relevant models to decipher the underlying mechanisms and ultimately find new treatments specific to fibrosis happening in cardiovascular diseases. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Myocardial Disease)
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