Cardiac Growth Control and Heart Cell Death

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Cardiovascular System".

Deadline for manuscript submissions: closed (5 September 2022) | Viewed by 28783

Special Issue Editors


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Guest Editor
Department of Physiology & Pathophysiology, and Pharmacology & Therapeutics, University of Manitoba, Winnipeg, MB, Canada
Interests: mitochondria; cell death; apoptosis; necrosis; autophagy; metabolism; ischemia-reperfusion; hypoxia; nuclear factor-kappa beta; heart failure

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Guest Editor
Department of Physiology and Pathophysiology, The Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada
Interests: cardiology; circadian rhythm; neurodegenerative disease

Special Issue Information

Dear Colleagues,

The adult heart has a limited capacity for de novo cardiac myocyte regeneration and/or self-renewal after injury. Heart disease is the most common cause of death worldwide, and programmed cell death is postulated as a central underlying cause of ventricular remodeling and heart failure. The mitochondrion has emerged as a central platform for regulating signaling events that govern cell growth, apoptosis, necrosis and quality control mechanisms by autophagy. These highly coordinated cellular processes share common and overlapping pathways; however, the intersection of how these pathways underlie cardiac dysfunction and disease pathogenesis remains poorly understood. Therefore, studies directed toward understanding the genetic, molecular and cellular mechanisms that underlie cardiac growth and programmed cell death in the heart are of paramount importance toward the ultimate therapeutic goal of developing new therapies that will prevent cardiovascular disease. Furthermore, there is growing appreciation that the incidence and severity of heart disease are different among women and men, with the prevalence of catastrophic outcomes following myocardial infarction dependent on the body’s biological clock and circadian rhythms.

Cells will publish a Special Issue in spring 2022 titled “Cardiac Growth Control and Heart Cell Death” that will solicit original research articles and reviews highlighting new exciting findings in the area of cardiac growth control and cell death. These exciting and innovative studies will have profound clinical implications for understanding the signaling mechanisms that underlie cell death following cardiac injury. We invite submissions of novel, exciting research on broad topics in cardiovascular health and disease, including, but not limited to, autophagy, cell death, mitochondrial quality control, women's heart health, circadian-regulated cardiac function and genetic studies on approaches related to cardiovascular disease mechanisms and potential therapies. Each submitted manuscript will go through a rigorous peer-review process. Submitted manuscripts must not have been published previously nor be under consideration for publication in other journals.

Prof. Dr. Lorrie Kirshenbaum
Dr. Inna Rabinovich-Nikitin
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. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • cell death
  • apoptosis
  • necrosis
  • autophagy
  • mitochondria
  • cardiac injury
  • cardiac metabolism
  • women heart health
  • circadian rhythm

Published Papers (10 papers)

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Research

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14 pages, 3065 KiB  
Article
NF-κB p65 Attenuates Cardiomyocyte PGC-1α Expression in Hypoxia
by Inna Rabinovich-Nikitin, Alexandra Blant, Rimpy Dhingra, Lorrie A. Kirshenbaum and Michael P. Czubryt
Cells 2022, 11(14), 2193; https://doi.org/10.3390/cells11142193 - 13 Jul 2022
Cited by 8 | Viewed by 2080
Abstract
Hypoxia exerts broad effects on cardiomyocyte function and viability, ranging from altered metabolism and mitochondrial physiology to apoptotic or necrotic cell death. The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a key regulator of cardiomyocyte metabolism and mitochondrial function and [...] Read more.
Hypoxia exerts broad effects on cardiomyocyte function and viability, ranging from altered metabolism and mitochondrial physiology to apoptotic or necrotic cell death. The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a key regulator of cardiomyocyte metabolism and mitochondrial function and is down-regulated in hypoxia; however, the underlying mechanism is incompletely resolved. Using primary rat cardiomyocytes coupled with electrophoretic mobility shift and luciferase assays, we report that hypoxia impaired mitochondrial energetics and resulted in an increase in nuclear localization of the Nuclear Factor-κB (NF-κB) p65 subunit, and the association of p65 with the PGC-1α proximal promoter. Tumor necrosis factor α (TNFα), an activator of NF-κB signaling, similarly reduced PGC-1α expression and p65 binding to the PGC-1α promoter in a dose-dependent manner, and TNFα-mediated down-regulation of PGC-1α expression could be reversed by the NF-κB inhibitor parthenolide. RNA-seq analysis revealed that cardiomyocytes isolated from p65 knockout mice exhibited alterations in genes associated with chromatin remodeling. Decreased PGC-1α promoter transactivation by p65 could be partially reversed by the histone deacetylase inhibitor trichostatin A. These results implicate NF-κB signaling, and specifically p65, as a potent inhibitor of PGC-1α expression in cardiac myocyte hypoxia. Full article
(This article belongs to the Special Issue Cardiac Growth Control and Heart Cell Death)
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14 pages, 2822 KiB  
Article
Mcl-1 Differentially Regulates Autophagy in Response to Changes in Energy Status and Mitochondrial Damage
by Alexandra G. Moyzis, Navraj S. Lally, Wenjing Liang, Rita H. Najor and Åsa B. Gustafsson
Cells 2022, 11(9), 1469; https://doi.org/10.3390/cells11091469 - 27 Apr 2022
Cited by 6 | Viewed by 2597
Abstract
Myeloid cell leukemia-1 (Mcl-1) is a unique antiapoptotic Bcl-2 member that is critical for mitochondrial homeostasis. Recent studies have demonstrated that Mcl-1′s functions extend beyond its traditional role in preventing apoptotic cell death. Specifically, data suggest that Mcl-1 plays a [...] Read more.
Myeloid cell leukemia-1 (Mcl-1) is a unique antiapoptotic Bcl-2 member that is critical for mitochondrial homeostasis. Recent studies have demonstrated that Mcl-1′s functions extend beyond its traditional role in preventing apoptotic cell death. Specifically, data suggest that Mcl-1 plays a regulatory role in autophagy, an essential degradation pathway involved in recycling and eliminating dysfunctional organelles. Here, we investigated whether Mcl-1 regulates autophagy in the heart. We found that cardiac-specific overexpression of Mcl-1 had little effect on baseline autophagic activity but strongly suppressed starvation-induced autophagy. In contrast, Mcl-1 did not inhibit activation of autophagy during myocardial infarction or mitochondrial depolarization. Instead, overexpression of Mcl-1 increased the clearance of depolarized mitochondria by mitophagy independent of Parkin. The increase in mitophagy was partially mediated via Mcl-1′s LC3-interacting regions and mutation of these sites significantly reduced Mcl-1-mediated mitochondrial clearance. We also found that Mcl-1 interacted with the mitophagy receptor Bnip3 and that the interaction was increased in response to mitochondrial stress. Overall, these findings suggest that Mcl-1 suppresses nonselective autophagy during nutrient limiting conditions, whereas it enhances selective autophagy of dysfunctional mitochondria by functioning as a mitophagy receptor. Full article
(This article belongs to the Special Issue Cardiac Growth Control and Heart Cell Death)
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10 pages, 1761 KiB  
Article
Cardiac Remodeling in the Absence of Cardiac Contractile Dysfunction Is Sufficient to Promote Cancer Progression
by Lama Awwad, Tomer Goldenberg, Irina Langier-Goncalves and Ami Aronheim
Cells 2022, 11(7), 1108; https://doi.org/10.3390/cells11071108 - 25 Mar 2022
Cited by 9 | Viewed by 2110
Abstract
Cardiovascular diseases and cancer are the leading cause of death worldwide. The two diseases share high co-prevalence and affect each other’s outcomes. Recent studies suggest that heart failure promotes cancer progression, although the question of whether cardiac remodeling in the absence of cardiac [...] Read more.
Cardiovascular diseases and cancer are the leading cause of death worldwide. The two diseases share high co-prevalence and affect each other’s outcomes. Recent studies suggest that heart failure promotes cancer progression, although the question of whether cardiac remodeling in the absence of cardiac contractile dysfunction promotes cancer progression remains unanswered. Here, we aimed to examine whether mild cardiac remodeling can promote tumor growth. We used low-phenylephrine (PE)-dose-infused in mice, together with breast cancer cells (polyoma middle T, PyMT), implanted in the mammary fat pad. Although cardiac remodeling, hypertrophy and fibrosis gene hallmarks were identified, echocardiography indicated no apparent loss of cardiac function. Nevertheless, in PE-infused mouse models, PyMT-cell-derived tumors grew larger and displayed increased cell proliferation. Consistently, serum derived from PE-infused mice resulted in increased cancer cell proliferation in vitro. ELISA and gene expression analysis identified periostin, fibronectin and CTGF as cardiac- and tumor-secreted factors that are highly abundant in PE-infused mice serum as compared with non-infused mice. Collectively, a low dose of PE infusion without the deterioration of cardiac function is sufficient to promote cancer progression. Hence, early detection and treatment of hypertension in healthy and cancer patients would be beneficial for improved outcomes. Full article
(This article belongs to the Special Issue Cardiac Growth Control and Heart Cell Death)
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Review

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19 pages, 963 KiB  
Review
Angiotensin II-Induced Signal Transduction Mechanisms for Cardiac Hypertrophy
by Sukhwinder K. Bhullar and Naranjan S. Dhalla
Cells 2022, 11(21), 3336; https://doi.org/10.3390/cells11213336 - 22 Oct 2022
Cited by 23 | Viewed by 3821
Abstract
Although acute exposure of the heart to angiotensin (Ang II) produces physiological cardiac hypertrophy and chronic exposure results in pathological hypertrophy, the signal transduction mechanisms for these effects are of complex nature. It is now evident that the hypertrophic response is mediated by [...] Read more.
Although acute exposure of the heart to angiotensin (Ang II) produces physiological cardiac hypertrophy and chronic exposure results in pathological hypertrophy, the signal transduction mechanisms for these effects are of complex nature. It is now evident that the hypertrophic response is mediated by the activation of Ang type 1 receptors (AT1R), whereas the activation of Ang type 2 receptors (AT2R) by Ang II and Mas receptors by Ang-(1-7) exerts antihypertrophic effects. Furthermore, AT1R-induced activation of phospholipase C for stimulating protein kinase C, influx of Ca2+ through sarcolemmal Ca2+- channels, release of Ca2+ from the sarcoplasmic reticulum, and activation of sarcolemmal NADPH oxidase 2 for altering cardiomyocytes redox status may be involved in physiological hypertrophy. On the other hand, reduction in the expression of AT2R and Mas receptors, the release of growth factors from fibroblasts for the occurrence of fibrosis, and the development of oxidative stress due to activation of mitochondria NADPH oxidase 4 as well as the depression of nuclear factor erythroid-2 activity for the occurrence of Ca2+-overload and activation of calcineurin may be involved in inducing pathological cardiac hypertrophy. These observations support the view that inhibition of AT1R or activation of AT2R and Mas receptors as well as depression of oxidative stress may prevent or reverse the Ang II-induced cardiac hypertrophy. Full article
(This article belongs to the Special Issue Cardiac Growth Control and Heart Cell Death)
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13 pages, 1040 KiB  
Review
Upregulation of Phospholipase C Gene Expression Due to Norepinephrine-Induced Hypertrophic Response
by Paramjit S. Tappia and Naranjan S. Dhalla
Cells 2022, 11(16), 2488; https://doi.org/10.3390/cells11162488 - 11 Aug 2022
Cited by 4 | Viewed by 1451
Abstract
The activation of phospholipase C (PLC) is thought to have a key role in the cardiomyocyte response to several different hypertrophic agents such as norepinephrine, angiotensin II and endothelin-1. PLC activity results in the generation of diacylglycerol and inositol trisphosphate, which are downstream [...] Read more.
The activation of phospholipase C (PLC) is thought to have a key role in the cardiomyocyte response to several different hypertrophic agents such as norepinephrine, angiotensin II and endothelin-1. PLC activity results in the generation of diacylglycerol and inositol trisphosphate, which are downstream signal transducers for the expression of fetal genes, increased protein synthesis, and subsequent cardiomyocyte growth. In this article, we describe the signal transduction elements that regulate PLC gene expression. The discussion is focused on the norepinephrine- α1-adrenoceptor signaling pathway and downstream signaling processes that mediate an upregulation of PLC isozyme gene expression. Evidence is also indicated to demonstrate that PLC activities self-regulate the expression of PLC isozymes with the suggestion that PLC activities may be part of a coordinated signaling process for the perpetuation of cardiac hypertrophy. Accordingly, from the information provided, it is plausible that specific PLC isozymes could be targeted for the mitigation of cardiac hypertrophy. Full article
(This article belongs to the Special Issue Cardiac Growth Control and Heart Cell Death)
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16 pages, 2055 KiB  
Review
Mitochondria and Doxorubicin-Induced Cardiomyopathy: A Complex Interplay
by Leonardo Schirone, Luca D’Ambrosio, Maurizio Forte, Riccardo Genovese, Sonia Schiavon, Giulia Spinosa, Giuliano Iacovone, Valentina Valenti, Giacomo Frati and Sebastiano Sciarretta
Cells 2022, 11(13), 2000; https://doi.org/10.3390/cells11132000 - 22 Jun 2022
Cited by 25 | Viewed by 4039
Abstract
Cardiotoxicity has emerged as a major side effect of doxorubicin (DOX) treatment, affecting nearly 30% of patients within 5 years after chemotherapy. Heart failure is the first non-cancer cause of death in DOX-treated patients. Although many different molecular mechanisms explaining the cardiac derangements [...] Read more.
Cardiotoxicity has emerged as a major side effect of doxorubicin (DOX) treatment, affecting nearly 30% of patients within 5 years after chemotherapy. Heart failure is the first non-cancer cause of death in DOX-treated patients. Although many different molecular mechanisms explaining the cardiac derangements induced by DOX were identified in past decades, the translation to clinical practice has remained elusive to date. This review examines the current understanding of DOX-induced cardiomyopathy (DCM) with a focus on mitochondria, which were increasingly proven to be crucial determinants of DOX-induced cytotoxicity. We discuss DCM pathophysiology and epidemiology and DOX-induced detrimental effects on mitochondrial function, dynamics, biogenesis, and autophagy. Lastly, we review the current perspectives to contrast the development of DCM, which is still a relatively diffused, invalidating, and life-threatening condition for cancer survivors. Full article
(This article belongs to the Special Issue Cardiac Growth Control and Heart Cell Death)
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9 pages, 888 KiB  
Review
Calreticulin and the Heart
by Jody Groenendyk, Wen-An Wang, Alison Robinson and Marek Michalak
Cells 2022, 11(11), 1722; https://doi.org/10.3390/cells11111722 - 24 May 2022
Cited by 6 | Viewed by 1990
Abstract
Calreticulin is an endoplasmic Ca2+ binding protein and molecular chaperone. As a cardiac embryonic gene, calreticulin is essential for heart development. The protein supports Ca2+-dependent signaling events that are critical to cardiomyocyte differentiation and cardiogenesis. The increased expression of calreticulin [...] Read more.
Calreticulin is an endoplasmic Ca2+ binding protein and molecular chaperone. As a cardiac embryonic gene, calreticulin is essential for heart development. The protein supports Ca2+-dependent signaling events that are critical to cardiomyocyte differentiation and cardiogenesis. The increased expression of calreticulin and endoplasmic reticulum/sarcoplasmic reticulum Ca2+ capacity produces cardiomyocytes with enhanced efficiency, and detrimental mechanical stretching of cardiac fibroblasts, leading to cardiac pathology. Deletion of the calreticulin gene in adult cardiomyocytes results in left ventricle dilation, an impaired electrocardiogram, and heart failure. These observations indicate that a well-adjusted endoplasmic reticulum and calreticulin-dependent Ca2+ pool in cardiomyocytes are critical for the maintenance of proper cardiac function. Full article
(This article belongs to the Special Issue Cardiac Growth Control and Heart Cell Death)
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14 pages, 1460 KiB  
Review
Circadian Governance of Cardiac Growth
by Mary N. Latimer and Martin E. Young
Cells 2022, 11(9), 1494; https://doi.org/10.3390/cells11091494 - 29 Apr 2022
Cited by 7 | Viewed by 2405
Abstract
The cardiomyocyte circadian clock temporally governs fundamental cellular processes, leading to 24-h rhythms in cardiac properties (such as electrophysiology and contractility). The importance of this cell-autonomous clock is underscored by reports that the disruption of the mechanism leads to adverse cardiac remodeling and [...] Read more.
The cardiomyocyte circadian clock temporally governs fundamental cellular processes, leading to 24-h rhythms in cardiac properties (such as electrophysiology and contractility). The importance of this cell-autonomous clock is underscored by reports that the disruption of the mechanism leads to adverse cardiac remodeling and heart failure. In healthy non-stressed mice, the cardiomyocyte circadian clock modestly augments both cardiac protein synthesis (~14%) and mass (~11%) at the awake-to-sleep transition (relative to their lowest values in the middle of the awake period). However, the increased capacity for cardiac growth at the awake-to-sleep transition exacerbates the responsiveness of the heart to pro-hypertrophic stimuli/stresses (e.g., adrenergic stimulation, nutrients) at this time. The cardiomyocyte circadian clock orchestrates time-of-day-dependent rhythms in cardiac growth through numerous mechanisms. Both ribosomal RNA (e.g., 28S) and the PI3K/AKT/mTOR/S6 signaling axis are circadian regulated, peaking at the awake-to-sleep transition in the heart. Conversely, the negative regulators of translation (including PER2, AMPK, and the integrated stress response) are elevated in the middle of the awake period in a coordinated fashion. We speculate that persistent circadian governance of cardiac growth during non-dipping/nocturnal hypertension, sleep apnea, and/or shift work may exacerbate left ventricular hypertrophy and cardiac disease development, highlighting a need for the advancement of chronotherapeutic interventions. Full article
(This article belongs to the Special Issue Cardiac Growth Control and Heart Cell Death)
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15 pages, 1013 KiB  
Review
The Role of Ferroptosis in Adverse Left Ventricular Remodeling Following Acute Myocardial Infarction
by Kyoko Komai, Nicholas K. Kawasaki, Jason K. Higa and Takashi Matsui
Cells 2022, 11(9), 1399; https://doi.org/10.3390/cells11091399 - 20 Apr 2022
Cited by 16 | Viewed by 3413
Abstract
Ferroptosis is an iron-dependent form of regulated cell death and is distinct from other conventional forms of regulated cell death. It is often characterized by the dysfunction of the antioxidant selenoprotein glutathione peroxidase 4 (GPX4) antioxidant system. This loss of antioxidant capacity leads [...] Read more.
Ferroptosis is an iron-dependent form of regulated cell death and is distinct from other conventional forms of regulated cell death. It is often characterized by the dysfunction of the antioxidant selenoprotein glutathione peroxidase 4 (GPX4) antioxidant system. This loss of antioxidant capacity leads to the peroxidation of lipids and subsequent compromised plasma membrane structure. Disruption of the GPX4 antioxidant system has been associated with various conditions such as cardiomyopathy and ischemia-reperfusion (I/R) injury. GPX4 regulates lipid peroxidation, and chemical or genetic inhibition of GPX4 leads to reduced cardiac function. Iron chelators or antioxidants can be used for inhibiting ferroptosis, which restores functionality in in vivo and ex vivo experiments and confers overall cardioprotective effects against I/R injury. Moreover, suppression of ferroptosis also suppresses inflammation and limits the extent of left ventricle remodeling after I/R injury. Future research is necessary to understand the role of ferroptosis following an ischemic incident and can lead to the discovery of more potential therapeutics that prevent ferroptosis in the heart. Full article
(This article belongs to the Special Issue Cardiac Growth Control and Heart Cell Death)
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9 pages, 686 KiB  
Review
Primary Cilia and Their Role in Acquired Heart Disease
by Zachariah E. Hale and Junichi Sadoshima
Cells 2022, 11(6), 960; https://doi.org/10.3390/cells11060960 - 11 Mar 2022
Cited by 2 | Viewed by 3451
Abstract
Primary cilia are non-motile plasma membrane extrusions that display a variety of receptors and mechanosensors. Loss of function results in ciliopathies, which have been strongly linked with congenital heart disease, as well as abnormal development and function of most organ systems. Adults with [...] Read more.
Primary cilia are non-motile plasma membrane extrusions that display a variety of receptors and mechanosensors. Loss of function results in ciliopathies, which have been strongly linked with congenital heart disease, as well as abnormal development and function of most organ systems. Adults with congenital heart disease have high rates of acquired heart failure, and usually die from a cardiac cause. Here we explore primary cilia’s role in acquired heart disease. Intraflagellar Transport 88 knockout results in reduced primary cilia, and knockout from cardiac endothelium produces myxomatous degeneration similar to mitral valve prolapse seen in adult humans. Induced primary cilia inactivation by other mechanisms also produces excess myocardial hypertrophy and altered scar architecture after ischemic injury, as well as hypertension due to a lack of vascular endothelial nitric oxide synthase activation and the resultant left ventricular dysfunction. Finally, primary cilia have cell-to-cell transmission capacity which, when blocked, leads to progressive left ventricular hypertrophy and heart failure, though this mechanism has not been fully established. Further research is still needed to understand primary cilia’s role in adult cardiac pathology, especially heart failure. Full article
(This article belongs to the Special Issue Cardiac Growth Control and Heart Cell Death)
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