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Cell Death in Cardiovascular Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (16 August 2023) | Viewed by 9987

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Special Issue Editors

Dr. Jason M. Karch

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Guest Editor

Cardiovascular Research Institute, Department of Integrative Physiology, Baylor College of Medicine, One Baylor Plaza (BCM335), Houston, TX 77030, USA
Interests: necrosis; apoptosis; autophagy; ferroptosis; pyroptosis; parthanatos; necroptosis; netosis; mitochondrial dysfunction

Dr. Joseph W. Gordon

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Guest Editor

Children's Hospital Research Institute of Manitoba, Winnipeg, MB R3E 3P4, Canada
Interests: Nix; Bnip3; myocardin; mitochondria; lipotoxicity; hypoxia; mitophagy; permeability transition; cell death; differentiation; proliferation; nutrition and metabolism; insulin signaling; cardiac; skeletal; vascular smooth muscle cells; rhabdomyosarcoma

Special Issue Information

Dear Colleagues,

Cell death is the driving force behind many forms of cardiovascular disease. Given the limited regenerative capacity of the heart, any cardiomyocyte loss during acute injury or chronic illness will have profound effects on cardiac remodeling and function. Further delineation of the various cell death pathways that contribute to cardiovascular disease is required for their therapeutic targeting, in order to fortify the heart and preserve life. For this Special Issue, we are recruiting both manuscripts or review articles that focus on cardiac cell death—any “-osis” is welcome. Everyone from early career academics to established investigators are encouraged to submit insightful works on the topic of cell death.

Dr. Jason M. Karch
Dr. Joseph W. Gordon
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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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Published Papers (5 papers)

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Research

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23 pages, 6506 KiB

Open AccessArticle

Ryanodine Receptor Staining Identifies Viable Cardiomyocytes in Human and Rabbit Cardiac Tissue Slices

by Ann-Katrin M. Pfeuffer, Linda K. Küpfer, Thirupura S. Shankar, Stavros G. Drakos, Tilmann Volk and Thomas Seidel

Int. J. Mol. Sci. 2023, 24(17), 13514; https://doi.org/10.3390/ijms241713514 - 31 Aug 2023

Cited by 1 | Viewed by 1537

Abstract

In terms of preserving multicellularity and myocardial function in vitro, the cultivation of beating myocardial slices is an emerging technique in basic and translational cardiac research. It can be used, for example, for drug screening or to study pathomechanisms. Here, we describe staining for viable cardiomyocytes based on the immunofluorescence of ryanodine receptors (RyRs) in human and rabbit myocardial slices. Biomimetic chambers were used for culture and measurements of contractile force. Fixable fluorophore-conjugated dextran, entering cells with a permeable membrane, was used for death staining. RyRs, nuclei and the extracellular matrix, including the t-system, were additionally stained and analyzed by confocal microscopy and image processing. We found the mutual exclusion of the RyR and dextran signals in cultivated slices. T-System density and nucleus size were reduced in RyR-negative/dextran-positive myocytes. The fraction of RyR-positive myocytes and pixels correlated with the contractile force. In RyR-positive/dextran-positive myocytes, we found irregular RyR clusters and SERCA distribution patterns, confirmed by an altered power spectrum. We conclude that RyR immunofluorescence indicates viable cardiomyocytes in vibratome-cut myocardial slices, facilitating the detection and differential structural analysis of living vs. dead or dying myocytes. We suggest the loss of sarcoplasmic reticulum integrity as an early event during cardiomyocyte death. Full article

(This article belongs to the Special Issue Cell Death in Cardiovascular Disease)

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19 pages, 5704 KiB

Open AccessArticle

The Impact of Semicarbazide Sensitive Amine Oxidase Activity on Rat Aortic Vascular Smooth Muscle Cells

by Vesna Manasieva, Shori Thakur, Lisa A. Lione, Anwar R. Baydoun and John Skamarauskas

Int. J. Mol. Sci. 2023, 24(5), 4946; https://doi.org/10.3390/ijms24054946 - 3 Mar 2023

Viewed by 1557

Abstract

Semicarbazide-sensitive amine oxidase (SSAO) is both a soluble- and membrane-bound transmembrane protein expressed in the vascular endothelial and in smooth muscle cells. In vascular endothelial cells, SSAO contributes to the development of atherosclerosis by mediating a leukocyte adhesion cascade; however, its contributory role in the development of atherosclerosis in VSMCs has not yet been fully explored. This study investigates SSAO enzymatic activity in VSMCs using methylamine and aminoacetone as model substrates. The study also addresses the mechanism by which SSAO catalytic activity causes vascular damage, and further evaluates the contribution of SSAO in oxidative stress formation in the vascular wall. SSAO demonstrated higher affinity for aminoacetone when compared to methylamine (Km = 12.08 µM vs. 65.35 µM). Aminoacetone- and methylamine-induced VSMCs death at concentrations of 50 & 1000 µM, and their cytotoxic effect, was reversed with 100 µM of the irreversible SSAO inhibitor MDL72527, which completely abolished cell death. Cytotoxic effects were also observed after 24 h of exposure to formaldehyde, methylglyoxal and H₂O₂. Enhanced cytotoxicity was detected after the simultaneous addition of formaldehyde and H₂O₂, as well as methylglyoxal and H₂O₂. The highest ROS production was observed in aminoacetone- and benzylamine-treated cells. MDL72527 abolished ROS in benzylamine-, methylamine- and aminoacetone-treated cells (**** p < 0.0001), while βAPN demonstrated inhibitory potential only in benzylamine-treated cells (* p < 0.05). Treatment with benzylamine, methylamine and aminoacetone reduced the total GSH levels (**** p < 0.0001); the addition of MDL72527 and βAPN failed to reverse this effect. Overall, a cytotoxic consequence of SSAO catalytic activity was observed in cultured VSMCs where SSAO was identified as a key mediator in ROS formation. These findings could potentially associate SSAO activity with the early developing stages of atherosclerosis through oxidative stress formation and vascular damage. Full article

(This article belongs to the Special Issue Cell Death in Cardiovascular Disease)

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16 pages, 2048 KiB

Open AccessArticle

Lethal Caspase-1/4-Dependent Injury Occurs in the First Minutes of Coronary Reperfusion and Requires Calpain Activity

by Xi-Ming Yang, Michael V. Cohen, Sarah Sayner, Jonathon P. Audia and James M. Downey

Int. J. Mol. Sci. 2023, 24(4), 3801; https://doi.org/10.3390/ijms24043801 - 14 Feb 2023

Cited by 3 | Viewed by 1308

Abstract

To study the relationship between caspase-1/4 and reperfusion injury, we measured infarct size (IS) in isolated mouse hearts undergoing 50 min global ischemia/2 h reperfusion. Starting VRT-043198 (VRT) at reperfusion halved IS. The pan-caspase inhibitor emricasan duplicated VRT’s protection. IS in caspase-1/4-knockout hearts was similarly reduced, supporting the hypothesis that caspase-1/4 was VRT’s only protective target. NLRC4 inflammasomes activate caspase-1. NLRC4 knockout hearts were not protected, eliminating NLRC4 as caspase-1/4’s activator. The amount of protection that could be achieved by only suppressing caspase-1/4 activity was limited. In wild-type (WT) hearts, ischemic preconditioning (IPC) was as protective as caspase-1/4 inhibitors. Combining IPC and emricasan in these hearts or preconditioning caspase-1/4-knockout hearts produced an additive IS reduction, indicating that more protection could be achieved by combining treatments. We determined when caspase-1/4 exerted its lethal injury. Starting VRT after 10 min of reperfusion in WT hearts was no longer protective, revealing that caspase-1/4 inflicted its injury within the first 10 min of reperfusion. Ca⁺⁺ influx at reperfusion might activate caspase-1/4. We tested whether Ca⁺⁺-dependent soluble adenylyl cyclase (AC10) could be responsible. However, IS in AC10^−/− hearts was not different from that in WT control hearts. Ca⁺⁺-activated calpain has been implicated in reperfusion injury. Calpain could be releasing actin-bound procaspase-1 in cardiomyocytes, which would explain why caspase-1/4-related injury is confined to early reperfusion. The calpain inhibitor calpeptin duplicated emricasan’s protection. Unlike IPC, adding calpain to emricasan offered no additional protection, suggesting that caspase-1/4 and calpain may share the same protective target. Full article

(This article belongs to the Special Issue Cell Death in Cardiovascular Disease)

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Review

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54 pages, 4229 KiB

Open AccessReview

New Dawn for Atherosclerosis: Vascular Endothelial Cell Senescence and Death

by Lan-Lan Bu, Huan-Huan Yuan, Ling-Li Xie, Min-Hua Guo, Duan-Fang Liao and Xi-Long Zheng

Int. J. Mol. Sci. 2023, 24(20), 15160; https://doi.org/10.3390/ijms242015160 - 13 Oct 2023

Cited by 6 | Viewed by 3621

Abstract

Endothelial cells (ECs) form the inner linings of blood vessels, and are directly exposed to endogenous hazard signals and metabolites in the circulatory system. The senescence and death of ECs are not only adverse outcomes, but also causal contributors to endothelial dysfunction, an early risk marker of atherosclerosis. The pathophysiological process of EC senescence involves both structural and functional changes and has been linked to various factors, including oxidative stress, dysregulated cell cycle, hyperuricemia, vascular inflammation, and aberrant metabolite sensing and signaling. Multiple forms of EC death have been documented in atherosclerosis, including autophagic cell death, apoptosis, pyroptosis, NETosis, necroptosis, and ferroptosis. Despite this, the molecular mechanisms underlying EC senescence or death in atherogenesis are not fully understood. To provide a comprehensive update on the subject, this review examines the historic and latest findings on the molecular mechanisms and functional alterations associated with EC senescence and death in different stages of atherosclerosis. Full article

(This article belongs to the Special Issue Cell Death in Cardiovascular Disease)

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30 pages, 1778 KiB

Open AccessReview

Clinical Applications for Gasotransmitters in the Cardiovascular System: Are We There Yet?

by Elisa Arrigo, Stefano Comità, Pasquale Pagliaro, Claudia Penna and Daniele Mancardi

Int. J. Mol. Sci. 2023, 24(15), 12480; https://doi.org/10.3390/ijms241512480 - 5 Aug 2023

Cited by 1 | Viewed by 1238

Abstract

Ischemia is the underlying mechanism in a wide variety of acute and persistent pathologies. As such, understanding the fine intracellular events occurring during (and after) the restriction of blood supply is pivotal to improving the outcomes in clinical settings. Among others, gaseous signaling molecules constitutively produced by mammalian cells (gasotransmitters) have been shown to be of potential interest for clinical treatment of ischemia/reperfusion injury. Nitric oxide (NO and its sibling, HNO), hydrogen sulfide (H₂S), and carbon monoxide (CO) have long been proven to be cytoprotective in basic science experiments, and they are now awaiting confirmation with clinical trials. The aim of this work is to review the literature and the clinical trials database to address the state of development of potential therapeutic applications for NO, H₂S, and CO and the clinical scenarios where they are more promising. Full article

(This article belongs to the Special Issue Cell Death in Cardiovascular Disease)

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