Hyperglycemia Induces Endoplasmic Reticulum Stress in Atrial Cardiomyocytes, and Mitofusin-2 Downregulation Prevents Mitochondrial Dysfunction and Subsequent Cell Death.

Ming Yuan,Mengqi Gong,Yue Zhang,Xing Liu,Guangping Li,Gary Tse,Qiankun Bao,Lei Meng,Yungang Zhao,Meng Yuan,Tong Liu,Zhiwei Zhang,Jos P Andrade

doi:10.1155/2020/6569728

Abstract

Mitochondrial oxidative stress and dysfunction play an important role of atrial remodeling and atrial fibrillation (AF) in diabetes mellitus. Endoplasmic reticulum (ER) stress has been linked to both physiological and pathological states including diabetes. The aim of this project is to explore the roles of ER stress in hyperglycemia-induced mitochondrial dysfunction and cell death of atrial cardiomyocytes. High glucose upregulated ER stress, mitochondrial oxidative stress, and mitochondria-associated ER membrane (MAM)- enriched proteins (such as glucose-regulated protein 75 (GRP75) and mitofusin-2 (Mfn2)) of primary cardiomyocytes in vitro. Sodium phenylbutyrate (4-PBA) prevented the above changes. Silencing of Mfn2 in HL-1 cells decreased the Ca2+ transfer from ER to mitochondria under ER stress conditions, which were induced by the ER stress agonist, tunicamycin (TM). Electron microscopy data suggested that Mfn2 siRNA significantly disrupted ER-mitochondria tethering in ER stress-injured HL-1 cells. Mfn2 silencing attenuated mitochondrial oxidative stress and Ca2+ overload, increased mitochondrial membrane potential and mitochondrial oxygen consumption, and protected cells from TM-induced apoptosis. In summary, Mfn2 plays an important role in high glucose-induced ER stress in atrial cardiomyocytes, and Mfn2 silencing prevents mitochondrial Ca2+ overload-mediated mitochondrial dysfunction, thereby decreasing ER stress-mediated cardiomyocyte cell death.

Highlights

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans and is associated with a fivefold increase in the risk of stroke
Considering the role of Mfn2 at the endoplasmic reticulum (ER)-mitochondrial interface in atrial cardiomyocytes, we demonstrate that Mfn2 silencing prevents mitochondrial Ca2+ overload-mediated mitochondrial dysfunction, thereby decreasing ER stress-mediated cell death of cardiomyocytes
Elevated glucose environment produced a significant increase in the levels of glucoseregulated protein 78 (GRP78) and C/EBP-homologous protein (CHOP) mRNA expression (Figure 1(a))

Summary

Introduction

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans and is associated with a fivefold increase in the risk of stroke. Numerous risk factors have been shown to promote AF, among which is diabetes mellitus (DM) [1, 2]. Numerous studies have implicated that oxidative stress are interrelated pathways that promote atrial electrical and structural remodeling, leading to atrial ectopy and interstitial fibrosis [3, 4]. The ensuing mitochondrial dysfunction and DNA damage are key to the progression of different cardiovascular diseases, including diabetic cardiomyopathy and AF. ER stress has been associated with both physiological and pathological conditions in the cardiovascular system including myocardial infarction, heart failure, hypoxia/reoxygenation injury, and dilated cardiomyopathy [5]. It is increasingly recognized that ER stress and unfolded protein response (UPR) pathways contribute to the pathogenesis of Oxidative Medicine and Cellular Longevity metabolic diseases such as diabetes [6]. Questions remain as to whether ER stress contributes to mitochondrial oxidative stress and ROS production in the context of diabetes

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