Dataset Information

LncRNA-ZFAS1 induces mitochondria-mediated apoptosis by causing cytosolic Ca²⁺ overload in myocardial infarction mice model.

ABSTRACT: Previously, we have identified ZFAS1 as a potential new long non-coding RNA (lncRNA) biomarker of acute myocardial infarction (MI) and as a sarcoplasmic reticulum Ca²⁺-ATPase 2a (SERCA2a) inhibitor, causing intracellular Ca²⁺ overload and contractile dysfunction in a mouse model of MI. In the current study, we aimed to evaluate the effects of ZFAS1 on the apoptosis of cardiomyocytes in the MI mouse model. Knockdown of endogenous ZFAS1 by virus-mediated silencing shRNA or siZFAS1 partially abrogated the ischemia-induced apoptosis of cardiomyocytes. Overexpression of ZFAS1 in normal cardiomyocytes reduced the cell viability, similar to that observed in hypoxia-treated cardiomyocytes. Moreover, ZFAS1 cardiac-specific knock-in mice showed impaired cardiac function, adversely altered Ca²⁺ homeostasis, repressed expression and activities of SERCA2a, and increased apoptosis. At the subcellular level, ZFAS1 induced mitochondrial swelling and showed a pronounced decrease in mitochondrial membrane potential. At the molecular level, ZFAS1 activated the mitochondria apoptosis pathway, which could be nearly abolished by a calcium chelator. The effects of ZFAS1 were readily reversible upon knockdown of this lncRNA. Notably, ZFAS1-FD (only functional domain) mimicked the effects of full-length ZFAS1 in regulation of cardiomyocyte apoptosis. In conclusion, our study shows that ZFAS1, an endogenous SERCA2a inhibitor, induces mitochondria-mediated apoptosis via cytosolic Ca²⁺ overload. Therefore, anti-ZFAS1 might be considered a new therapeutic strategy for protecting cardiomyocytes from MI-induced apoptosis.

SUBMITTER: Jiao L

PROVIDER: S-EPMC6901475 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

lncRNA-ZFAS1 induces mitochondria-mediated apoptosis by causing cytosolic Ca2+ overload in myocardial infarction mice model.

Jiao Lei L Li Mengmeng M Shao Yingchun Y Zhang Yuanyuan Y Gong Manyu M Yang Xuewen X Wang Yanying Y Tan Zhongyue Z Sun Lihua L Xuan Lina L Yu Qi Q Li Yanru Y Gao Yuqiu Y Liu Heng H Xu Honglin H Li Xiaohan X Zhang Yong Y Zhang Ying Y

Cell death & disease 20191209 12

Previously, we have identified ZFAS1 as a potential new long non-coding RNA (lncRNA) biomarker of acute myocardial infarction (MI) and as a sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) inhibitor, causing intracellular Ca2+ overload and contractile dysfunction in a mouse model of MI. In the current study, we aimed to evaluate the effects of ZFAS1 on the apoptosis of cardiomyocytes in the MI mouse model. Knockdown of endogenous ZFAS1 by virus-mediated silencing shRNA or si ...[more]

PMID: 31819041

Similar Datasets

Project description:Mitochondrial Ca2+ handling is accomplished by balancing Ca2+ uptake, primarily via the Ru360-sensitive mitochondrial calcium uniporter (MCU), Ca2+ buffering in the matrix and Ca2+ efflux mainly via Ca2+ ion exchangers, such as the Na+/Ca2+ exchanger (NCLX) and the Ca2+/H+ exchanger (CHE). The mechanism of CHE in cardiac mitochondria is not well-understood and its contribution to matrix Ca2+ regulation is thought to be negligible, despite higher expression of the putative CHE protein, LETM1, compared to hepatic mitochondria. In this study, Ca2+ efflux via the CHE was investigated in isolated rat cardiac mitochondria and permeabilized H9c2 cells. Mitochondria were exposed to (a) increasing matrix Ca2+ load via repetitive application of a finite CaCl2 bolus to the external medium and (b) change in the pH gradient across the inner mitochondrial membrane (IMM). Ca2+ efflux at different matrix Ca2+ loads was revealed by inhibiting Ca2+ uptake or reuptake with Ru360 after increasing number of CaCl2 boluses. In Na+-free experimental buffer and with Ca2+ uptake inhibited, the rate of Ca2+ efflux and steady-state free matrix Ca2+ [mCa2+]ss increased as the number of administered CaCl2 boluses increased. ADP and cyclosporine A (CsA), which are known to increase Ca2+ buffering while maintaining a constant [mCa2+]ss, decreased the rate of Ca2+ efflux via the CHE, with a significantly greater decrease in the presence of ADP. ADP also increased Ca2+ buffering rate and decreased [mCa2+]ss. A change in the pH of the external medium to a more acidic value from 7.15 to 6.8∼6.9 caused a twofold increase in the Ca2+ efflux rate, while an alkaline change in pH from 7.15 to 7.4∼7.5 did not change the Ca2+ efflux rate. In addition, CHE activation was associated with membrane depolarization. Targeted transient knockdown of LETM1 in permeabilized H9c2 cells modulated Ca2+ efflux. The results indicate that Ca2+ efflux via the CHE in cardiac mitochondria is modulated by acidic buffer pH and by total matrix Ca2+. A mechanism is proposed whereby activation of CHE is sensitive to changes in both the matrix Ca2+ buffering system and the matrix free Ca2+ concentration.

Project description:Ventricular arrhythmogenesis is a key cause of sudden cardiac death following myocardial infarction (MI). Accumulating data show that ischemia, sympathetic activation, and inflammation contribute to arrhythmogenesis. However, the role and mechanisms of abnormal mechanical stress in ventricular arrhythmia following MI remain undefined. We aimed to examine the impact of increased mechanical stress and identify the role of the key sensor Piezo1 in ventricular arrhythmogenesis in MI. Concomitant with increased ventricular pressure, Piezo1, as a newly recognized mechano-sensitive cation channel, was the most up-regulated mechanosensor in the myocardium of patients with advanced heart failure. Piezo1 was mainly located at the intercalated discs and T-tubules of cardiomyocytes, which are responsible for intracellular calcium homeostasis and intercellular communication. Cardiomyocyte-conditional Piezo1 knockout mice (Piezo1Cko) exhibited preserved cardiac function after MI. Piezo1Cko mice also displayed a dramatically decreased mortality in response to the programmed electrical stimulation after MI with a markedly reduced incidence of ventricular tachycardia. In contrast, activation of Piezo1 in mouse myocardium increased the electrical instability as indicated by prolonged QT interval and sagging ST segment. Mechanistically, Piezo1 impaired intracellular calcium cycling dynamics by mediating the intracellular Ca2+ overload and increasing the activation of Ca2+-modulated signaling, CaMKII, and calpain, which led to the enhancement of phosphorylation of RyR2 and further increment of Ca2+ leaking, finally provoking cardiac arrhythmias. Furthermore, in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), Piezo1 activation remarkably triggered cellular arrhythmogenic remodeling by significantly shortening the duration of the action potential, inducing early afterdepolarization, and enhancing triggered activity.This study uncovered a proarrhythmic role of Piezo1 during cardiac remodeling, which is achieved by regulating Ca2+ handling, implying a promising therapeutic target in sudden cardiac death and heart failure.

Dataset Information

LncRNA-ZFAS1 induces mitochondria-mediated apoptosis by causing cytosolic Ca²⁺ overload in myocardial infarction mice model.

Publications

lncRNA-ZFAS1 induces mitochondria-mediated apoptosis by causing cytosolic Ca<sup>2+</sup> overload in myocardial infarction mice model.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

LncRNA-ZFAS1 induces mitochondria-mediated apoptosis by causing cytosolic Ca2+ overload in myocardial infarction mice model.

Publications

lncRNA-ZFAS1 induces mitochondria-mediated apoptosis by causing cytosolic Ca<sup>2+</sup> overload in myocardial infarction mice model.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

LncRNA-ZFAS1 induces mitochondria-mediated apoptosis by causing cytosolic Ca²⁺ overload in myocardial infarction mice model.