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11 pages, 2410 KiB

Open AccessArticle

Activation of Immune System May Cause Pathophysiological Changes in the Myocardium of SARS-CoV-2 Infected Monkey Model

by Maryam Yahya Rabbani, Jay Rappaport and Manish Kumar Gupta

Cells 2022, 11(4), 611; https://doi.org/10.3390/cells11040611 - 10 Feb 2022

Viewed by 3142

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is an extremely contagious disease whereby the virus damages the host’s respiratory tract via entering through the ACE2 receptor. Cardiovascular disorder is being recognized in the majority of COVID-19 patients; yet, the relationship between SARS-CoV-2 [...] Read more.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is an extremely contagious disease whereby the virus damages the host’s respiratory tract via entering through the ACE2 receptor. Cardiovascular disorder is being recognized in the majority of COVID-19 patients; yet, the relationship between SARS-CoV-2 and heart failure has not been established. In the present study, SARS-CoV-2 infection was induced in the monkey model. Thereafter, heart tissue samples were collected, and pathological changes were analyzed in the left ventricular tissue by hematoxylin and eosin, trichrome, and immunohistochemical staining specific to T lymphocytes and macrophages. The findings revealed that SARS-CoV-2 infection induces several pathological changes in the heart, which cause cardiomyocyte disarray, mononuclear infiltrates of inflammatory cells, and hypertrophy. Furthermore, collagen-specific staining showed the development of cardiac fibrosis in the interstitial and perivascular regions in the hearts of infected primates. Moreover, the myocardial tissue samples displayed multiple foci of inflammatory cells positive for T lymphocytes and macrophages within the myocardium. These findings suggest the progression of the disease, which can lead to the development of severe complications, including heart failure. Additionally, SARS-CoV-2 antigen staining detected the presence of virus particles in the myocardium. Thus, we found that SARS-CoV-2 infection is characterized by an exaggerated inflammatory immune response in the heart, which possibly contributes to myocardial remodeling and subsequent fibrosis. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying Cardiac Dysfunction)

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15 pages, 2764 KiB

Open AccessArticle

Functional Inhibition of Valosin-Containing Protein Induces Cardiac Dilation and Dysfunction in a New Dominant-Negative Transgenic Mouse Model

by Xiaonan Sun, Ning Zhou, Ben Ma, Wenqian Wu, Shaunrick Stoll, Lo Lai, Gangjian Qin and Hongyu Qiu

Cells 2021, 10(11), 2891; https://doi.org/10.3390/cells10112891 - 26 Oct 2021

Cited by 6 | Viewed by 1799

Abstract

Valosin-containing protein (VCP) was found to play a vital protective role against cardiac stresses. Genetic mutations of VCP are associated with human dilated cardiomyopathy. However, the essential role of VCP in the heart during the physiological condition remains unknown since the VCP knockout [...] Read more.

Valosin-containing protein (VCP) was found to play a vital protective role against cardiac stresses. Genetic mutations of VCP are associated with human dilated cardiomyopathy. However, the essential role of VCP in the heart during the physiological condition remains unknown since the VCP knockout in mice is embryonically lethal. We generated a cardiac-specific dominant-negative VCP transgenic (DN-VCP TG) mouse to determine the effects of impaired VCP activity on the heart. Using echocardiography, we showed that cardiac-specific overexpression of DN-VCP induced a remarkable cardiac dilation and progressively declined cardiac function during the aging transition. Mechanistically, DN-VCP did not affect the endogenous VCP (EN-VCP) expression but significantly reduced cardiac ATPase activity in the DN-VCP TG mouse hearts, indicating a functional inhibition. DN-VCP significantly impaired the aging-related cytoplasmic/nuclear shuffling of EN-VCP and its co-factors in the heart tissues and interrupted the balance of the VCP-cofactors interaction between the activating co-factors, ubiquitin fusion degradation protein 1 (UFD-1)/nuclear protein localization protein 4 (NPL-4) complex, and its inhibiting co-factor P47, leading to the binding preference with the inhibitory co-factor, resulting in functional repression of VCP. This DN-VCP TG mouse provides a unique functional-inactivation model for investigating VCP in the heart in physiological and pathological conditions. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying Cardiac Dysfunction)

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21 pages, 52708 KiB

Open AccessArticle

iPLA₂β Contributes to ER Stress-Induced Apoptosis during Myocardial Ischemia/Reperfusion Injury

by Tingting Jin, Jun Lin, Yingchao Gong, Xukun Bi, Shasha Hu, Qingbo Lv, Jiaweng Chen, Xiaoting Li, Jiaqi Chen, Wenbin Zhang, Meihui Wang and Guosheng Fu

Cells 2021, 10(6), 1446; https://doi.org/10.3390/cells10061446 - 09 Jun 2021

Cited by 14 | Viewed by 3184

Abstract

Both calcium-independent phospholipase A2 beta (iPLA₂β) and endoplasmic reticulum (ER) stress regulate important pathophysiological processes including inflammation, calcium homeostasis and apoptosis. However, their roles in ischemic heart disease are poorly understood. Here, we show that the expression of iPLA₂β [...] Read more.

Both calcium-independent phospholipase A2 beta (iPLA₂β) and endoplasmic reticulum (ER) stress regulate important pathophysiological processes including inflammation, calcium homeostasis and apoptosis. However, their roles in ischemic heart disease are poorly understood. Here, we show that the expression of iPLA₂β is increased during myocardial ischemia/reperfusion (I/R) injury, concomitant with the induction of ER stress and the upregulation of cell death. We further show that the levels of iPLA₂β in serum collected from acute myocardial infarction (AMI) patients and in samples collected from both in vivo and in vitro I/R injury models are significantly elevated. Further, iPLA₂β knockout mice and siRNA mediated iPLA₂β knockdown are employed to evaluate the ER stress and cell apoptosis during I/R injury. Additionally, cell surface protein biotinylation and immunofluorescence assays are used to trace and locate iPLA₂β. Our data demonstrate the increase of iPLA₂β augments ER stress and enhances cardiomyocyte apoptosis during I/R injury in vitro and in vivo. Inhibition of iPLA₂β ameliorates ER stress and decreases cell death. Mechanistically, iPLA₂β promotes ER stress and apoptosis by translocating to ER upon myocardial I/R injury. Together, our study suggests iPLA₂β contributes to ER stress-induced apoptosis during myocardial I/R injury, which may serve as a potential therapeutic target against ischemic heart disease. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying Cardiac Dysfunction)

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14 pages, 6780 KiB

Open AccessArticle

Dysbindin deficiency Alters Cardiac BLOC-1 Complex and Myozap Levels in Mice

by Ankush Borlepawar, Nesrin Schmiedel, Matthias Eden, Lynn Christen, Alexandra Rosskopf, Derk Frank, Renate Lüllmann-Rauch, Norbert Frey and Ashraf Yusuf Rangrez

Cells 2020, 9(11), 2390; https://doi.org/10.3390/cells9112390 - 31 Oct 2020

Cited by 2 | Viewed by 2071

Abstract

Dysbindin, a schizophrenia susceptibility marker and an essential constituent of BLOC-1 (biogenesis of lysosome-related organelles complex-1), has recently been associated with cardiomyocyte hypertrophy through the activation of Myozap-RhoA-mediated SRF signaling. We employed sandy mice (Dtnbp1_KO), which completely lack Dysbindin protein because [...] Read more.

Dysbindin, a schizophrenia susceptibility marker and an essential constituent of BLOC-1 (biogenesis of lysosome-related organelles complex-1), has recently been associated with cardiomyocyte hypertrophy through the activation of Myozap-RhoA-mediated SRF signaling. We employed sandy mice (Dtnbp1_KO), which completely lack Dysbindin protein because of a spontaneous deletion of introns 5–7 of the Dtnbp1 gene, for pathophysiological characterization of the heart. Unlike in vitro, the loss-of-function of Dysbindin did not attenuate cardiac hypertrophy, either in response to transverse aortic constriction stress or upon phenylephrine treatment. Interestingly, however, the levels of hypertrophy-inducing interaction partner Myozap as well as the BLOC-1 partners of Dysbindin like Muted and Pallidin were dramatically reduced in Dtnbp1_KO mouse hearts. Taken together, our data suggest that Dysbindin’s role in cardiomyocyte hypertrophy is redundant in vivo, yet essential to maintain the stability of its direct interaction partners like Myozap, Pallidin and Muted. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying Cardiac Dysfunction)

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Review

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12 pages, 1428 KiB

Open AccessReview

Noncoding RNAs in Cardiac Hypertrophy and Heart Failure

by Peilei Lu, Fan Ding, Yang Kevin Xiang, Liying Hao and Meimi Zhao

Cells 2022, 11(5), 777; https://doi.org/10.3390/cells11050777 - 23 Feb 2022

Cited by 21 | Viewed by 3166

Abstract

Heart failure is a major global health concern. Noncoding RNAs (ncRNAs) are involved in physiological processes and in the pathogenesis of various diseases, including heart failure. ncRNAs have emerged as critical components of transcriptional regulatory pathways that govern cardiac development, stress response, signaling, [...] Read more.

Heart failure is a major global health concern. Noncoding RNAs (ncRNAs) are involved in physiological processes and in the pathogenesis of various diseases, including heart failure. ncRNAs have emerged as critical components of transcriptional regulatory pathways that govern cardiac development, stress response, signaling, and remodeling in cardiac pathology. Recently, studies of ncRNAs in cardiovascular disease have achieved significant development. Here, we discuss the roles of ncRNAs, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) that modulate the cardiac hypertrophy and heart failure. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying Cardiac Dysfunction)

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14 pages, 1051 KiB

Open AccessReview

Role of Irisin in Myocardial Infarction, Heart Failure, and Cardiac Hypertrophy

by Ming-Yun Ho and Chao-Yung Wang

Cells 2021, 10(8), 2103; https://doi.org/10.3390/cells10082103 - 16 Aug 2021

Cited by 48 | Viewed by 6620

Abstract

Irisin is a myokine derived from the cleavage of fibronectin type III domain-containing 5. Irisin regulates mitochondrial energy, glucose metabolism, fatty acid oxidation, and fat browning. Skeletal muscle and cardiomyocytes produce irisin and affect various cardiovascular functions. In the early phase of acute [...] Read more.

Irisin is a myokine derived from the cleavage of fibronectin type III domain-containing 5. Irisin regulates mitochondrial energy, glucose metabolism, fatty acid oxidation, and fat browning. Skeletal muscle and cardiomyocytes produce irisin and affect various cardiovascular functions. In the early phase of acute myocardial infarction, an increasing irisin level can reduce endothelial damage by inhibiting inflammation and oxidative stress. By contrast, higher levels of irisin in the later phase of myocardial infarction are associated with more cardiovascular events. During different stages of heart failure, irisin has various influences on mitochondrial dysfunction, oxidative stress, metabolic imbalance, energy expenditure, and heart failure prognosis. Irisin affects blood pressure and controls hypertension through modulating vasodilatation. Moreover, irisin can enhance vasoconstriction via the hypothalamus. Because of these dual effects of irisin on cardiovascular physiology, irisin can be a critical therapeutic target in cardiovascular diseases. This review focuses on the complex functions of irisin in myocardial ischemia, heart failure, and cardiac hypertrophy. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying Cardiac Dysfunction)

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17 pages, 1450 KiB

Open AccessFeature PaperReview

Calpain-Mediated Mitochondrial Damage: An Emerging Mechanism Contributing to Cardiac Disease

by Mengxiao Zhang, Grace Wang and Tianqing Peng

Cells 2021, 10(8), 2024; https://doi.org/10.3390/cells10082024 - 08 Aug 2021

Cited by 18 | Viewed by 5033

Abstract

Calpains belong to the family of calcium-dependent cysteine proteases expressed ubiquitously in mammals and many other organisms. Activation of calpain is observed in diseased hearts and is implicated in cardiac cell death, hypertrophy, fibrosis, and inflammation. However, the underlying mechanisms remain incompletely understood. [...] Read more.

Calpains belong to the family of calcium-dependent cysteine proteases expressed ubiquitously in mammals and many other organisms. Activation of calpain is observed in diseased hearts and is implicated in cardiac cell death, hypertrophy, fibrosis, and inflammation. However, the underlying mechanisms remain incompletely understood. Recent studies have revealed that calpains target and impair mitochondria in cardiac disease. The objective of this review is to discuss the role of calpains in mediating mitochondrial damage and the underlying mechanisms, and to evaluate whether targeted inhibition of mitochondrial calpain is a potential strategy in treating cardiac disease. We expect to describe the wealth of new evidence surrounding calpain-mediated mitochondrial damage to facilitate future mechanistic studies and therapy development for cardiac disease. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying Cardiac Dysfunction)

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17 pages, 1720 KiB

Open AccessReview

Role of Neutrophils in Cardiac Injury and Repair Following Myocardial Infarction

by Yonggang Ma

Cells 2021, 10(7), 1676; https://doi.org/10.3390/cells10071676 - 02 Jul 2021

Cited by 43 | Viewed by 6853

Abstract

Neutrophils are first-line responders of the innate immune system. Following myocardial infarction (MI), neutrophils are quickly recruited to the ischemic region, where they initiate the inflammatory response, aiming at cleaning up dead cell debris. However, excessive accumulation and/or delayed removal of neutrophils are [...] Read more.

Neutrophils are first-line responders of the innate immune system. Following myocardial infarction (MI), neutrophils are quickly recruited to the ischemic region, where they initiate the inflammatory response, aiming at cleaning up dead cell debris. However, excessive accumulation and/or delayed removal of neutrophils are deleterious. Neutrophils can promote myocardial injury by releasing reactive oxygen species, granular components, and pro-inflammatory mediators. More recent studies have revealed that neutrophils are able to form extracellular traps (NETs) and produce extracellular vesicles (EVs) to aggravate inflammation and cardiac injury. On the contrary, there is growing evidence showing that neutrophils also exert anti-inflammatory, pro-angiogenic, and pro-reparative effects, thus facilitating inflammation resolution and cardiac repair. In this review, we summarize the current knowledge on neutrophils’ detrimental roles, highlighting the role of recently recognized NETs and EVs, followed by a discussion of their beneficial effects and molecular mechanisms in post-MI cardiac remodeling. In addition, emerging concepts about neutrophil diversity and their modulation of adaptive immunity are discussed. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying Cardiac Dysfunction)

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27 pages, 3540 KiB

Open AccessReview

Molecular Mechanisms of Obesity-Linked Cardiac Dysfunction: An Up-Date on Current Knowledge

by Jorge Gutiérrez-Cuevas, Ana Sandoval-Rodriguez, Alejandra Meza-Rios, Hugo Christian Monroy-Ramírez, Marina Galicia-Moreno, Jesús García-Bañuelos, Arturo Santos and Juan Armendariz-Borunda

Cells 2021, 10(3), 629; https://doi.org/10.3390/cells10030629 - 12 Mar 2021

Cited by 58 | Viewed by 5680

Abstract

Obesity is defined as excessive body fat accumulation, and worldwide obesity has nearly tripled since 1975. Excess of free fatty acids (FFAs) and triglycerides in obese individuals promote ectopic lipid accumulation in the liver, skeletal muscle tissue, and heart, among others, inducing insulin [...] Read more.

Obesity is defined as excessive body fat accumulation, and worldwide obesity has nearly tripled since 1975. Excess of free fatty acids (FFAs) and triglycerides in obese individuals promote ectopic lipid accumulation in the liver, skeletal muscle tissue, and heart, among others, inducing insulin resistance, hypertension, metabolic syndrome, type 2 diabetes (T2D), atherosclerosis, and cardiovascular disease (CVD). These diseases are promoted by visceral white adipocyte tissue (WAT) dysfunction through an increase in pro-inflammatory adipokines, oxidative stress, activation of the renin-angiotensin-aldosterone system (RAAS), and adverse changes in the gut microbiome. In the heart, obesity and T2D induce changes in substrate utilization, tissue metabolism, oxidative stress, and inflammation, leading to myocardial fibrosis and ultimately cardiac dysfunction. Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of carbohydrate and lipid metabolism, also improve insulin sensitivity, triglyceride levels, inflammation, and oxidative stress. The purpose of this review is to provide an update on the molecular mechanisms involved in obesity-linked CVD pathophysiology, considering pro-inflammatory cytokines, adipokines, and hormones, as well as the role of oxidative stress, inflammation, and PPARs. In addition, cell lines and animal models, biomarkers, gut microbiota dysbiosis, epigenetic modifications, and current therapeutic treatments in CVD associated with obesity are outlined in this paper. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying Cardiac Dysfunction)

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