Cardiac Piezo1 Exacerbates Lethal Ventricular Arrhythmogenesis by Linking Mechanical Stress with Ca(2+) Handling After Myocardial Infarction.
Cardiac Piezo1 Exacerbates Lethal Ventricular Arrhythmogenesis by Linking Mechanical Stress with Ca(2+) Handling After Myocardial Infarction.
复制标题
DOI：
10.34133/research.0165
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Xiang M
中科院分区：
文献类型：
--
作者：
Su SA;Zhang Y;Li W;Xi Y;Lu Y;Shen J;Ma Y;Wang Y;Shen Y;Xie L;Ma H;Xie Y;Xiang M
心室肌纤维化是心肌梗死（MI）后心源性猝死的重要原因。越来越多的数据表明，缺血、交感神经激活和炎症有助于动脉瘤的发生。然而，异常机械应力在MI后室性心律失常中的作用和机制仍不清楚。我们的目的是检查机械应力增加的影响，并确定关键传感器Piezo 1在心肌梗死心室肌发生中的作用。Piezo 1作为一种新发现的机械敏感性阳离子通道，在晚期心力衰竭患者心肌中上调最多，与心室压力升高相伴。Piezo 1主要定位于心肌细胞的闰盘和T管，负责细胞内钙稳态和细胞间通讯。心肌细胞条件性Piezo 1基因敲除小鼠（Piezo 1Cko）在MI后表现出保留的心脏功能。Piezo 1Cko小鼠在MI后对程控电刺激的反应中也显示出显著降低的死亡率，室性心动过速的发生率显著降低。相反，小鼠心肌中Piezo 1的激活增加了电不稳定性，如QT间期延长和ST段下垂所示。Piezo 1通过介导细胞内Ca 2+超载和增加Ca 2+调节信号、CaMKII和钙蛋白酶的激活来损害细胞内钙循环动力学，从而导致RyR 2磷酸化增强和Ca 2+泄漏进一步增加，最终引起心律失常。此外，在人诱导多能干细胞衍生的心肌细胞中，在hiPSC-CMs中，Piezo 1激活通过显著缩短动作电位持续时间、诱导早期后除极和增强触发活动而显著触发细胞致心律失常重构。本研究揭示了Piezo 1在心脏重构中的促心律失常作用，其通过调节Ca 2+处理来实现，这意味着在心脏性猝死和心力衰竭中有希望的治疗靶点。
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.
登录
查看更多内容
机械敏感的 Piezo1 通道介导心脏机械-化学转导
影响因子：
16.6
作者：
Jiang F;Yin K;Wu K;Zhang M;Wang S;Cheng H;Zhou Z;Xiao B
通讯作者：
Xiao B
DOI：
10.1073/pnas.0908540107
发表时间：
2010-01-26
影响因子：
11.1
作者：
Fauconnier, Jeremy;Thireau, Jerome;Lacampagne, Alain
通讯作者：
Lacampagne, Alain
影响因子：
4.4
作者：
Liu, Chinky Shiu Chen;Raychaudhuri, Deblina;Ganguly, Dipyaman
通讯作者：
Ganguly, Dipyaman
影响因子：
24
作者：
Patterson, E;Lazzara, R;Po, SS
通讯作者：
Po, SS
心脏ryanodine受体的CAMKII依赖性磷酸化调节心脏缺血/再灌注损伤中的细胞死亡。
影响因子：
5
作者：
Di Carlo, Mariano N.;Said, Matilde;Ling, Haiyun;Valverde, Carlos A.;De Giusti, Veronica C.;Sommese, Leandro;Palomeque, Julieta;Aiello, Ernesto A.;Skapura, Darlene G.;Rinaldi, Gustavo;Respress, Jonathan L.;Brown, Joan Heller;Wehrens, Xander H. T.;Salas, Margarita A.;Mattiazzi, Alicia
通讯作者：
Mattiazzi, Alicia