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16 pages, 1019 KiB

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The Role of BAG3 Protein Interactions in Cardiomyopathies

by Hui-Qi Qu, Ju-Fang Wang, Alexandre Rosa-Campos, Hakon Hakonarson and Arthur M. Feldman

Int. J. Mol. Sci. 2024, 25(20), 11308; https://doi.org/10.3390/ijms252011308 - 21 Oct 2024

Cited by 1 | Viewed by 1635

Abstract

Bcl-2-associated athanogene 3 (BAG3) plays an important function in cellular protein quality control (PQC) maintaining proteome stability. Mutations in the BAG3 gene result in cardiomyopathies. Due to its roles in cardiomyopathies and the complexity of BAG3–protein interactions, it is important to understand these [...] Read more.

Bcl-2-associated athanogene 3 (BAG3) plays an important function in cellular protein quality control (PQC) maintaining proteome stability. Mutations in the BAG3 gene result in cardiomyopathies. Due to its roles in cardiomyopathies and the complexity of BAG3–protein interactions, it is important to understand these protein interactions given the importance of the multifunctional cochaperone BAG3 in cardiomyocytes, using an in vitro cardiomyocyte model. The experimental assay was conducted using high pressure liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) in the human AC16 cardiomyocyte cell line with BioID technology. Proteins with BAG3-interaction were identified in all the 28 hallmark gene sets enriched in idiopathic cardiomyopathies and/or ischemic disease. Among the 24 hallmark gene sets enriched in both idiopathic cardiomyopathies and ischemic disease, 15 gene sets had at least 3 proteins with BAG3-interaction. This study highlights BAG3 protein interactions, unveiling the key gene sets affected in cardiomyopathies, which help to explain the molecular mechanisms of the cardioprotective effects of BAG3. In addition, this study also highlighted the complexity of proteins with BAG3 interactions, implying unwanted effects of BAG3. Full article

(This article belongs to the Special Issue Current Research for Heart Disease Biology and Therapeutics: 2nd Edition)

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Review

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15 pages, 1564 KiB

Open AccessReview

Epigenetics in Heart Failure

by Jamie Sin Ying Ho, Eric Jou, Pek-Lan Khong, Roger S. Y. Foo and Ching-Hui Sia

Int. J. Mol. Sci. 2024, 25(22), 12010; https://doi.org/10.3390/ijms252212010 - 8 Nov 2024

Cited by 2 | Viewed by 2070

Abstract

Heart failure is a clinical syndrome with rising global incidence and poor prognosis despite improvements in medical therapy. There is increasing research interest in epigenetic therapies for heart failure. Pathological cardiac remodelling may be driven by stress-activated cardiac signalling cascades, and emerging research [...] Read more.

Heart failure is a clinical syndrome with rising global incidence and poor prognosis despite improvements in medical therapy. There is increasing research interest in epigenetic therapies for heart failure. Pathological cardiac remodelling may be driven by stress-activated cardiac signalling cascades, and emerging research has shown the involvement of epigenetic signals that regulate transcriptional changes leading to heart failure. In this review, we appraise the current evidence for the role of epigenetic modifications in heart failure. These include DNA methylation and histone modifications by methylation, acetylation, phosphorylation, ubiquitination and sumoylation, which are critical processes that establish an epigenetic pattern and translate environmental stress into genetic expression, leading to cardiac remodeling. We summarize the potential epigenetic therapies currently in development, including the limited clinical trials of epigenetic therapies in heart failure. The dynamic changes in the epigenome in the disease process require further elucidation, and so does the impact of this process on the development of therapeutics. Understanding the role of epigenetics in heart failure may pave the way for the identification of novel biomarkers and molecular targets, and facilitate the development of personalized therapies for this important condition. Full article

(This article belongs to the Special Issue Current Research for Heart Disease Biology and Therapeutics: 2nd Edition)

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19 pages, 991 KiB

Open AccessReview

Space Travel: The Radiation and Microgravity Effects on the Cardiovascular System

by Andrei Alexandru Mircea, Dan Valentin Pistritu, Andra Fortner, Antoanela Tanca, Elisa Anamaria Liehn and Octavian Bucur

Int. J. Mol. Sci. 2024, 25(21), 11812; https://doi.org/10.3390/ijms252111812 - 3 Nov 2024

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Abstract

Space flight modulates the functions of the cardiovascular system. The exposure to space conditions can alter the cerebral blood flow, as well as the venous return. Anemia, cardiac output changes, and increased activity of the sympathetic nervous system can also be seen. Understanding [...] Read more.

Space flight modulates the functions of the cardiovascular system. The exposure to space conditions can alter the cerebral blood flow, as well as the venous return. Anemia, cardiac output changes, and increased activity of the sympathetic nervous system can also be seen. Understanding cardiac changes prepares astronauts for both better in-flight adaptations and long-term protection against cardiovascular diseases. The heart could undergo radio-degenerative effects when exposed to space radiation, increasing the risk of cardiovascular diseases in the long run. A high frequency of arrhythmias, such as ventricular/atrial premature complexes, have been reported during the Gemini and Apollo missions. Additionally, microgravity can lead to progressive degeneration of the myocytes and muscle atrophy with altered gene expression and calcium handling, along with impaired contractility. This review summarizes the potential cardiovascular effects of spaceflight and prevention measures. Full article

(This article belongs to the Special Issue Current Research for Heart Disease Biology and Therapeutics: 2nd Edition)

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39 pages, 4675 KiB

Open AccessReview

Recent Insights into Endogenous Mammalian Cardiac Regeneration Post-Myocardial Infarction

by Erika Fiorino, Daniela Rossin, Roberto Vanni, Matteo Aubry, Claudia Giachino and Raffaella Rastaldo

Int. J. Mol. Sci. 2024, 25(21), 11747; https://doi.org/10.3390/ijms252111747 - 1 Nov 2024

Cited by 2 | Viewed by 2446

Abstract

Myocardial infarction (MI) is a critical global health issue and a leading cause of heart failure. Indeed, while neonatal mammals can regenerate cardiac tissue mainly through cardiomyocyte proliferation, this ability is lost shortly after birth, resulting in the adult heart’s inability to regenerate [...] Read more.

Myocardial infarction (MI) is a critical global health issue and a leading cause of heart failure. Indeed, while neonatal mammals can regenerate cardiac tissue mainly through cardiomyocyte proliferation, this ability is lost shortly after birth, resulting in the adult heart’s inability to regenerate after injury effectively. In adult mammals, the adverse cardiac remodelling, which compensates for the loss of cardiac cells, impairs cardiac function due to the non-contractile nature of fibrotic tissue. Moreover, the neovascularisation after MI is inadequate to restore blood flow to the infarcted myocardium. This review aims to synthesise the most recent insights into the molecular and cellular players involved in endogenous myocardial and vascular regeneration, facilitating the identification of mechanisms that could be targeted to trigger cardiac regeneration, reduce fibrosis, and improve functional recovery post-MI. Reprogramming adult cardiomyocytes to regain their proliferative potential, along with the modulation of target cells responsible for neovascularisation, represents promising therapeutic strategies. An updated overview of endogenous mechanisms that regulate both myocardial and coronary vasculature regeneration—including stem and progenitor cells, growth factors, cell cycle regulators, and key signalling pathways—could help identify new critical intervention points for therapeutic applications. Full article

(This article belongs to the Special Issue Current Research for Heart Disease Biology and Therapeutics: 2nd Edition)

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21 pages, 2552 KiB

Open AccessReview

Evolving Strategies for Extracellular Vesicles as Future Cardiac Therapeutics: From Macro- to Nano-Applications

by Laura Guerricchio, Lucio Barile and Sveva Bollini

Int. J. Mol. Sci. 2024, 25(11), 6187; https://doi.org/10.3390/ijms25116187 - 4 Jun 2024

Cited by 1 | Viewed by 2313

Abstract

Cardiovascular disease represents the foremost cause of mortality and morbidity worldwide, with a steadily increasing incidence due to the growth of the ageing population. Cardiac dysfunction leading to heart failure may arise from acute myocardial infarction (MI) as well as inflammatory- and cancer-related [...] Read more.

Cardiovascular disease represents the foremost cause of mortality and morbidity worldwide, with a steadily increasing incidence due to the growth of the ageing population. Cardiac dysfunction leading to heart failure may arise from acute myocardial infarction (MI) as well as inflammatory- and cancer-related chronic cardiomyopathy. Despite pharmacological progress, effective cardiac repair represents an unmet clinical need, with heart transplantation being the only option for end-stage heart failure. The functional profiling of the biological activity of extracellular vesicles (EVs) has recently attracted increasing interest in the field of translational research for cardiac regenerative medicine. The cardioprotective and cardioactive potential of human progenitor stem/cell-derived EVs has been reported in several preclinical studies, and EVs have been suggested as promising paracrine therapy candidates for future clinical translation. Nevertheless, some compelling aspects must be properly addressed, including optimizing delivery strategies to meet patient needs and enhancing targeting specificity to the cardiac tissue. Therefore, in this review, we will discuss the most relevant aspects of the therapeutic potential of EVs released by human progenitors for cardiovascular disease, with a specific focus on the strategies that have been recently implemented to improve myocardial targeting and administration routes. Full article

(This article belongs to the Special Issue Current Research for Heart Disease Biology and Therapeutics: 2nd Edition)

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19 pages, 867 KiB

Open AccessReview

Fibroblast Diversity and Epigenetic Regulation in Cardiac Fibrosis

by Laura Pilar Aguado-Alvaro, Nerea Garitano and Beatriz Pelacho

Int. J. Mol. Sci. 2024, 25(11), 6004; https://doi.org/10.3390/ijms25116004 - 30 May 2024

Cited by 7 | Viewed by 3509

Abstract

Cardiac fibrosis, a process characterized by excessive extracellular matrix (ECM) deposition, is a common pathological consequence of many cardiovascular diseases (CVDs) normally resulting in organ failure and death. Cardiac fibroblasts (CFs) play an essential role in deleterious cardiac remodeling and dysfunction. In response [...] Read more.

Cardiac fibrosis, a process characterized by excessive extracellular matrix (ECM) deposition, is a common pathological consequence of many cardiovascular diseases (CVDs) normally resulting in organ failure and death. Cardiac fibroblasts (CFs) play an essential role in deleterious cardiac remodeling and dysfunction. In response to injury, quiescent CFs become activated and adopt a collagen-secreting phenotype highly contributing to cardiac fibrosis. In recent years, studies have been focused on the exploration of molecular and cellular mechanisms implicated in the activation process of CFs, which allow the development of novel therapeutic approaches for the treatment of cardiac fibrosis. Transcriptomic analyses using single-cell RNA sequencing (RNA-seq) have helped to elucidate the high cellular diversity and complex intercellular communication networks that CFs establish in the mammalian heart. Furthermore, a significant body of work supports the critical role of epigenetic regulation on the expression of genes involved in the pathogenesis of cardiac fibrosis. The study of epigenetic mechanisms, including DNA methylation, histone modification, and chromatin remodeling, has provided more insights into CF activation and fibrotic processes. Targeting epigenetic regulators, especially DNA methyltransferases (DNMT), histone acetylases (HAT), or histone deacetylases (HDAC), has emerged as a promising approach for the development of novel anti-fibrotic therapies. This review focuses on recent transcriptomic advances regarding CF diversity and molecular and epigenetic mechanisms that modulate the activation process of CFs and their possible clinical applications for the treatment of cardiac fibrosis. Full article

(This article belongs to the Special Issue Current Research for Heart Disease Biology and Therapeutics: 2nd Edition)

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32 pages, 1356 KiB

Open AccessReview

Is Cardiac Transplantation Still a Contraindication in Patients with Muscular Dystrophy-Related End-Stage Dilated Cardiomyopathy? A Systematic Review

by Luisa Politano

Int. J. Mol. Sci. 2024, 25(10), 5289; https://doi.org/10.3390/ijms25105289 - 13 May 2024

Cited by 2 | Viewed by 2314

Abstract

Inherited muscular diseases (MDs) are genetic degenerative disorders typically caused by mutations in a single gene that affect striated muscle and result in progressive weakness and wasting in affected individuals. Cardiac muscle can also be involved with some variability that depends on the [...] Read more.

Inherited muscular diseases (MDs) are genetic degenerative disorders typically caused by mutations in a single gene that affect striated muscle and result in progressive weakness and wasting in affected individuals. Cardiac muscle can also be involved with some variability that depends on the genetic basis of the MD (Muscular Dystrophy) phenotype. Heart involvement can manifest with two main clinical pictures: left ventricular systolic dysfunction with evolution towards dilated cardiomyopathy and refractory heart failure, or the presence of conduction system defects and serious life-threatening ventricular arrhythmias. The two pictures can coexist. In these cases, heart transplantation (HTx) is considered the most appropriate option in patients who are not responders to the optimized standard therapeutic protocols. However, cardiac transplant is still considered a relative contraindication in patients with inherited muscle disorders and end-stage cardiomyopathies. High operative risk related to muscle impairment and potential graft involvement secondary to the underlying myopathy have been the two main reasons implicated in the generalized reluctance to consider cardiac transplant as a viable option. We report an overview of cardiac involvement in MDs and its possible association with the underlying molecular defect, as well as a systematic review of HTx outcomes in patients with MD-related end-stage dilated cardiomyopathy, published so far in the literature. Full article

(This article belongs to the Special Issue Current Research for Heart Disease Biology and Therapeutics: 2nd Edition)

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22 pages, 1370 KiB

Open AccessReview

Mechanisms of Pulmonary Vasculopathy in Acute and Long-Term COVID-19: A Review

by Marianne Riou, Florence Coste, Alain Meyer, Irina Enache, Samy Talha, Anne Charloux, Cyril Reboul and Bernard Geny

Int. J. Mol. Sci. 2024, 25(9), 4941; https://doi.org/10.3390/ijms25094941 - 30 Apr 2024

Cited by 8 | Viewed by 4124

Abstract

Despite the end of the pandemic, coronavirus disease 2019 (COVID-19) remains a major public health concern. The first waves of the virus led to a better understanding of its pathogenesis, highlighting the fact that there is a specific pulmonary vascular disorder. Indeed, COVID-19 [...] Read more.

Despite the end of the pandemic, coronavirus disease 2019 (COVID-19) remains a major public health concern. The first waves of the virus led to a better understanding of its pathogenesis, highlighting the fact that there is a specific pulmonary vascular disorder. Indeed, COVID-19 may predispose patients to thrombotic disease in both venous and arterial circulation, and many cases of severe acute pulmonary embolism have been reported. The demonstrated presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within the endothelial cells suggests that direct viral effects, in addition to indirect effects of perivascular inflammation and coagulopathy, may contribute to pulmonary vasculopathy in COVID-19. In this review, we discuss the pathological mechanisms leading to pulmonary vascular damage during acute infection, which appear to be mainly related to thromboembolic events, an impaired coagulation cascade, micro- and macrovascular thrombosis, endotheliitis and hypoxic pulmonary vasoconstriction. As many patients develop post-COVID symptoms, including dyspnea, we also discuss the hypothesis of pulmonary vascular damage and pulmonary hypertension as a sequela of the infection, which may be involved in the pathophysiology of long COVID. Full article

(This article belongs to the Special Issue Current Research for Heart Disease Biology and Therapeutics: 2nd Edition)

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