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      Diabetes aggravates myocardial ischaemia reperfusion injury via activating Nox2‐related programmed cell death in an AMPK‐dependent manner

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          Abstract

          Cardiovascular diseases such as myocardial ischaemia have a high fatality rate in patients with diabetes. This study was designed to expose the crosstalk between oxidative stress and AMPK, a vital molecule that controls biological energy metabolism, in myocardial ischaemia reperfusion injury (I/RI) in diabetic rats. Diabetes was stimulated in rats using streptozotocin injection. Rats were separated on random into control, control + I/R, Diabetes, Diabetes + I/R, Diabetes + I/R + N‐acetylcysteine and Diabetes + I/R + Vas2870 groups. Myocardial infarct size was determined, and the predominant Nox family isoforms were analysed. In vitro, the H9C2 cells were administered excess glucose and exposed to hypoxia/reoxygenation to mimic diabetes and I/R. The AMPK siRNA or AICAR was used to inhibit or activate AMPK expression in H9C2 cells, respectively. Then, myocardial oxidative stress and programmed cell death were measured. Diabetes or high glucose levels were found to aggravate myocardial I/RI or hypoxia/reoxygenation in H9C2 cells, as demonstrated by an increase in myocardial infarct size or lactate dehydrogenase levels, oxidative stress generation and induction of programmed cell death. In diabetic rat hearts, cardiac Nox1, Nox2 and Nox4 were all heightened. The suppression of Nox2 expression using Vas2870 or Nox2‐siRNA treatment in vivo or in vitro , respectively, protected diabetic rats from myocardial I/RI. AMPK gene knockout increased Nox2 protein expression while AMPK agonist decreased Nox2 expression. Therefore, diabetes aggravates myocardial I/RI by generating of Nox2‐associated oxidative stress in an AMPK‐dependent manner, which led to the induction of programmed cell death such as apoptosis, pyroptosis and ferroptosis.

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          Most cited references28

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

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            Ferroptosis Is a Type of Autophagy-Dependent Cell Death

            Macroautophagy (hereafter referred to as autophagy) involves an intracellular degradation and recycling system that, in a context-dependent manner, can either promote cell survival or accelerate cellular demise. Ferroptosis was originally defined in 2012 as an iron-dependent form of cancer cell death different from apoptosis, necrosis, and autophagy. However, this latter assumption came into question because, in response to ferroptosis activators (e.g., erastin and RSL3), autophagosomes accumulate, and because components of the autophagy machinery (e.g., ATG3, ATG5, ATG4B, ATG7, ATG13, and BECN1) contribute to ferroptotic cell death. In particular, NCOA4-facilitated ferritinophagy, RAB7A-dependent lipophagy, BECN1-mediated system xc- inhibition, STAT3-induced lysosomal membrane permeabilization, and HSP90-associated chaperone-mediated autophagy can promote ferroptosis. In this review, we summarize current knowledge on the signaling pathways involved in ferroptosis, while focusing on the regulation of autophagy-dependent ferroptotic cell death. The molecular comprehension of these phenomena may lead to the development of novel anticancer therapies.
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              Fundamental Mechanisms of Regulated Cell Death and Implications for Heart Disease

              Twelve regulated cell death programs have been described. We review in detail the basic biology of nine including death receptor-mediated apoptosis, death receptor-mediated necrosis (necroptosis), mitochondrial-mediated apoptosis, mitochondrial-mediated necrosis, autophagy-dependent cell death, ferroptosis, pyroptosis, parthanatos, and immunogenic cell death. This is followed by a dissection of the roles of these cell death programs in the major cardiac syndromes: myocardial infarction and heart failure. The most important conclusion relevant to heart disease is that regulated forms of cardiomyocyte death play important roles in both myocardial infarction with reperfusion (ischemia/reperfusion) and heart failure. While a role for apoptosis in ischemia/reperfusion cannot be excluded, regulated forms of necrosis, through both death receptor and mitochondrial pathways, are critical. Ferroptosis and parthanatos are also likely important in ischemia/reperfusion, although it is unclear if these entities are functioning as independent death programs or as amplification mechanisms for necrotic cell death. Pyroptosis may also contribute to ischemia/reperfusion injury, but potentially through effects in non-cardiomyocytes. Cardiomyocyte loss through apoptosis and necrosis is also an important component in the pathogenesis of heart failure and is mediated by both death receptor and mitochondrial signaling. Roles for immunogenic cell death in cardiac disease remain to be defined but merit study in this era of immune checkpoint cancer therapy. Biology-based approaches to inhibit cell death in the various cardiac syndromes are also discussed.
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                Author and article information

                Contributors
                luckydoczhang@163.com
                yaowf3@mail.sysu.edu.cn
                Journal
                J Cell Mol Med
                J. Cell. Mol. Med
                10.1111/(ISSN)1582-4934
                JCMM
                Journal of Cellular and Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1582-1838
                1582-4934
                29 April 2020
                June 2020
                : 24
                : 12 ( doiID: 10.1111/jcmm.v24.12 )
                : 6670-6679
                Affiliations
                [ 1 ] Department of Anesthesiology Shenzhen People's Hospital and Shenzhen Anesthesiology Engineering Center The Second Clinical Medical College of Jinan University Shenzhen China
                [ 2 ] Department of Pathophysiology School of Medicine Shenzhen University Shenzhen China
                [ 3 ] Department of Anesthesiology Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong China
                [ 4 ] Department of Anesthesiology The Third Affiliated Hospital of Sun Yat‐sen University Guangzhou China
                Author notes
                [*] [* ] Correspondence

                Zhongjun Zhang, Department of Anaesthesiology, Shenzhen People's Hospital; Shenzhen Anaesthesiology Engineering Center; the Second Clinical Medical College, Jinan University, Shenzhen, China.

                Email: luckydoczhang@ 123456163.com

                Weifeng Yao, Department of Anesthesiology, Third Affiliated Hospital, Sun Yat‐sen University, Guangzhou, Guangdong 510630, China.

                Email: yaowf3@ 123456mail.sysu.edu.cn

                Author information
                https://orcid.org/0000-0002-7002-5524
                https://orcid.org/0000-0002-5284-9159
                Article
                JCMM15318
                10.1111/jcmm.15318
                7299688
                32351005
                12dde9f8-5f95-4bf0-ac7c-443264c69f78
                © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 16 February 2020
                : 05 April 2020
                : 07 April 2020
                Page count
                Figures: 5, Tables: 0, Pages: 10, Words: 6314
                Funding
                Funded by: cooperative research and development program of Shenzhen people’s hospital
                Award ID: SYJY201709
                Funded by: Shenzhen Science and Technology Innovation Committee
                Award ID: JCYJ 20170307095506831(l.s.)
                Funded by: Shenzhen Science and Technology Innovation Committee
                Award ID: JCYJ20180305180809671
                Funded by: National Natural Science Foundation of China , open-funder-registry 10.13039/501100001809;
                Award ID: 81801947
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                June 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.4 mode:remove_FC converted:17.06.2020

                Molecular medicine
                ampk,diabetes,myocardial ischaemia reperfusion injury,nox2,programmed cell death

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