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      Guidelines for evaluating myocardial cell death

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          Abstract

          Cell death is a fundamental process in cardiac pathologies. Recent studies have revealed multiple forms of cell death, and several of them have been demonstrated to underlie adverse cardiac remodeling and heart failure. With the expansion in the area of myocardial cell death and increasing concerns over rigor and reproducibility, it is important and timely to set a guideline for the best practices of evaluating myocardial cell death. There are six major forms of regulated cell death observed in cardiac pathologies, namely apoptosis, necroptosis, mitochondrial-mediated necrosis, pyroptosis, ferroptosis, and autophagic cell death. In this article, we describe the best methods to identify, measure, and evaluate these modes of myocardial cell death. In addition, we discuss the limitations of currently practiced myocardial cell death mechanisms.

          Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/guidelines-for-evaluating-myocardial-cell-death/ .

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          Most cited references185

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          Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a Gasdermin

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            Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis.

            Enigmatic lipid peroxidation products have been claimed as the proximate executioners of ferroptosis-a specialized death program triggered by insufficiency of glutathione peroxidase 4 (GPX4). Using quantitative redox lipidomics, reverse genetics, bioinformatics and systems biology, we discovered that ferroptosis involves a highly organized oxygenation center, wherein oxidation in endoplasmic-reticulum-associated compartments occurs on only one class of phospholipids (phosphatidylethanolamines (PEs)) and is specific toward two fatty acyls-arachidonoyl (AA) and adrenoyl (AdA). Suppression of AA or AdA esterification into PE by genetic or pharmacological inhibition of acyl-CoA synthase 4 (ACSL4) acts as a specific antiferroptotic rescue pathway. Lipoxygenase (LOX) generates doubly and triply-oxygenated (15-hydroperoxy)-diacylated PE species, which act as death signals, and tocopherols and tocotrienols (vitamin E) suppress LOX and protect against ferroptosis, suggesting a homeostatic physiological role for vitamin E. This oxidative PE death pathway may also represent a target for drug discovery.
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              Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes.

              Apoptosis induced by TNF-receptor I (TNFR1) is thought to proceed via recruitment of the adaptor FADD and caspase-8 to the receptor complex. TNFR1 signaling is also known to activate the transcription factor NF-kappa B and promote survival. The mechanism by which this decision between cell death and survival is arbitrated is not clear. We report that TNFR1-induced apoptosis involves two sequential signaling complexes. The initial plasma membrane bound complex (complex I) consists of TNFR1, the adaptor TRADD, the kinase RIP1, and TRAF2 and rapidly signals activation of NF-kappa B. In a second step, TRADD and RIP1 associate with FADD and caspase-8, forming a cytoplasmic complex (complex II). When NF-kappa B is activated by complex I, complex II harbors the caspase-8 inhibitor FLIP(L) and the cell survives. Thus, TNFR1-mediated-signal transduction includes a checkpoint, resulting in cell death (via complex II) in instances where the initial signal (via complex I, NF-kappa B) fails to be activated.
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                Author and article information

                Journal
                American Journal of Physiology-Heart and Circulatory Physiology
                American Journal of Physiology-Heart and Circulatory Physiology
                American Physiological Society
                0363-6135
                1522-1539
                November 01 2019
                November 01 2019
                : 317
                : 5
                : H891-H922
                Affiliations
                [1 ]Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska
                [2 ]Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University of Bratislava, Bratislava, Slovakia
                [3 ]Departments of Medicine (Cardiology) and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas
                [4 ]Department of Biomedical Sciences, Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, Missouri
                [5 ]Cardiovascular Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
                [6 ]Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, Alabama
                [7 ]Mount Sinai Heart, Icahn School of Medicine at Mount Sinai Hospital, New York, New York
                [8 ]Division of Inflammation Research, Center of Molecular Medicine, Jichi Medical University, Tochigi, Japan
                [9 ]Virginia Commonwealth University, Pauley Heart Center, Richmond, Virginia
                [10 ]Department of Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, Texas
                [11 ]Department of Anatomy, Biochemistry, and Physiology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii
                Article
                10.1152/ajpheart.00259.2019
                6879915
                31418596
                4226a23e-6c97-4b61-be47-c5fcd8f88e7d
                © 2019
                History

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