Progressive Reduction in Myocyte Autophagy After Myocardial Infarction in Rabbits: Association with Oxidative Stress and Left Ventricular Remodeling

Chi, Rui‐Fang; Wang, Jia-Pu; Wang, Ke; Zhang, Xiaoli; Zhang, Yuean; Kang, Yu‐Ming; Han, Xiao; Bao, Li; Qin, Fuzhong; Fan, Bianai

doi:10.1159/000486167

Cited by 20 publications

(15 citation statements)

References 37 publications

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“…Following cardiac injury regardless of cause, oxidative stress contributes critically to pathological remodeling by fibrosis and the ensuing increased proarrhythmic risk at fibrotic border zones. Notably, increased oxidative stress to the heart may occur specifically post-infarction (Ide et al, 2001;Venditti et al, 2001;Carpi et al, 2009;Chi et al, 2017;Margaritis et al, 2017) and in heart failure (Nickel et al, 2015;Bertero and Maack, 2018b;Zhou and Tian, 2018). However, increased oxidative stress to the heart may also occur non-specifically in cardiac inflammation (Zhou et al, 2011), metabolic dysregulation (Nickel et al, 2015;Bertero and Maack, 2018a), and aging (Ander et al, 2007;Lisanti et al, 2011;Martín-Fernández and Gredilla, 2016).…”

Section: Dual Hits By Fibrosis and H 2 O 2 For Arrhythmogenic Synergymentioning

confidence: 99%

Proarrhythmic Electrical Remodeling by Noncardiomyocytes at Interfaces With Cardiomyocytes Under Oxidative Stress

et al. 2021

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Life-threatening ventricular arrhythmias, typically arising from interfaces between fibrosis and surviving cardiomyocytes, are feared sequelae of structurally remodeled hearts under oxidative stress. Incomplete understanding of the proarrhythmic electrical remodeling by fibrosis limits the development of novel antiarrhythmic strategies. To define the mechanistic determinants of the proarrhythmia in electrical crosstalk between cardiomyocytes and noncardiomyocytes, we developed a novel in vitro model of interface between neonatal rat ventricular cardiomyocytes (NRVMs) and controls [NRVMs or connexin43 (Cx43)-deficient HeLa cells] vs. Cx43+ noncardiomyocytes [aged rat ventricular myofibroblasts (ARVFs) or HeLaCx43 cells]. We performed high-speed voltage-sensitive optical imaging at baseline and following acute H2O2 exposure. In NRVM-NRVM and NRVM-HeLa controls, no arrhythmias occurred under either experimental condition. In the NRVM-ARVF and NRVM-HeLaCx43 groups, Cx43+ noncardiomyocytes enabled passive decremental propagation of electrical impulses and impaired NRVM activation and repolarization, thereby slowing conduction and prolonging action potential duration. Following H2O2 exposure, arrhythmia triggers, automaticity, and non-reentrant and reentrant arrhythmias emerged. This study reveals that myofibroblasts (which generate cardiac fibrosis) and other noncardiomyocytes can induce not only structural remodeling but also electrical remodeling and that electrical remodeling by noncardiomyocytes can be particularly arrhythmogenic in the presence of an oxidative burst. Synergistic electrical remodeling between H2O2 and noncardiomyocytes may account for the clinical arrhythmogenicity of myofibroblasts at fibrotic interfaces with cardiomyocytes in ischemic/non-ischemic cardiomyopathies. Understanding the enhanced arrhythmogenicity of synergistic electrical remodeling by H2O2 and noncardiomyocytes may guide novel safe-by-design antiarrhythmic strategies for next-generation iatrogenic interfaces between surviving native cardiomyocytes and exogenous stem cells or engineered tissues in cardiac regenerative therapies.

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Section: Dual Hits By Fibrosis and H 2 O 2 For Arrhythmogenic Synergymentioning

confidence: 99%

Proarrhythmic Electrical Remodeling by Noncardiomyocytes at Interfaces With Cardiomyocytes Under Oxidative Stress

et al. 2021

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“…The role of autophagy after MI is still controversial. Chi et al found that myocyte autophagy progressively decreased at 1, 4, and 8 weeks after MI, 23 but Yan et al found that the LC3-II/I ratio and Beclin 1 increased in chronic ischemic myocardium. 24 Mice with per2 overexpression showed high expression levels of LC3 (Fig.…”

Section: Overexpression Of Per2 Increases Myocardial Autophagy After MImentioning

confidence: 99%

Period 2-Induced Activation of Autophagy Improves Cardiac Remodeling After Myocardial Infarction

et al. 2020

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Accumulating evidence indicates that the onset of myocardial infarction (MI) shows obvious circadian rhythmicity. Clinical studies have shown that MIs that occur in the early morning have a poor prognosis, but the mechanisms involved are still unknown. In this study, we showed that the expression level of Period 2 (per2) in the heart of mice is lower in the early morning than at noon and that increasing the expression of per2 in H9C2 cells and rat cardiomyocytes increases autophagy levels. Further studies indicated that overexpression of per2 after an MI improved cardiac function by increasing autophagy. In summary, this study has shown that the circadian clock protein, per2, may be a regulator of MI.

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“…Myocardial infarct size was measured as described previously 30,31 . For the hearts used for biochemical assays, infarct size was estimated from the ratio of the infarct to the whole LV weights.…”

Section: Methodsmentioning

confidence: 99%

Apocynin prevents reduced myocardial nerve growth factor, contributing to amelioration of myocardial apoptosis and failure

Xiao

Yang

Wang

et al. 2021

Clin Exp Pharma Physio

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Reduced nerve growth factor (NGF) is associated with cardiac sympathetic nerve denervation in heart failure (HF) which is characterized by increased oxidative stress. Apocynin is considered an antioxidant agent which inhibits NADPH oxidase activity and improves reactive oxygen species scavenging. However, it is unclear whether apocynin prevents reduced myocardial NGF, leading to improvement of cardiac function in HF. In this study, we tested the hypothesis that apocynin prevents reduced myocardial NGF, contributing to amelioration of myocardial apoptosis and failure. Rabbits with myocardial infarction (MI) or sham operation were randomly assigned to receive apocynin or placebo for 4 weeks. MI rabbits exhibited left ventricular (LV) dysfunction, and elevation in oxidative stress, as evidenced by a decreased reduced‐to‐oxidized glutathione ratio and an increased 4‐hydroxynonenal expression, and reduction in NGF and NGF receptor tyrosine kinase A (TrKA) expression in the remote non‐infarcted myocardium. Apocynin treatment ameliorated LV dysfunction, reduced oxidative stress, prevented decreases in NGF and TrKA expression and reduced cardiomyocyte apoptosis after MI. In cultured H9C2 cardiomyocytes, hypoxia or hydrogen peroxide decreased NGF expression, and apocynin normalized hypoxia‐induced reduction of NGF. Recombinant NGF attenuated hypoxia‐induced apoptosis. Apocynin prevented hypoxia‐induced apoptosis, and the suppressive effect of apocynin on apoptosis was abolished by NGF receptor TrKA inhibitor K252a. We concluded that apocynin prevented reduced myocardial NGF, leading to attenuation of cardiomyocyte apoptosis and LV remodelling and dysfunction in HF after MI. These findings suggest that strategies to prevent NGF reduction by inhibition of oxidative stress may be of value in amelioration of LV dysfunction in HF.

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Progressive Reduction in Myocyte Autophagy After Myocardial Infarction in Rabbits: Association with Oxidative Stress and Left Ventricular Remodeling

Cited by 20 publications

References 37 publications

Proarrhythmic Electrical Remodeling by Noncardiomyocytes at Interfaces With Cardiomyocytes Under Oxidative Stress

Proarrhythmic Electrical Remodeling by Noncardiomyocytes at Interfaces With Cardiomyocytes Under Oxidative Stress

Period 2-Induced Activation of Autophagy Improves Cardiac Remodeling After Myocardial Infarction

Apocynin prevents reduced myocardial nerve growth factor, contributing to amelioration of myocardial apoptosis and failure

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