Piezo1-Mediated Mechanotransduction Promotes Cardiac Hypertrophy by Impairing Calcium Homeostasis to Activate Calpain/Calcineurin Signaling
Piezo1-Mediated Mechanotransduction Promotes Cardiac Hypertrophy by Impairing Calcium Homeostasis to Activate Calpain/Calcineurin Signaling
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DOI：
10.1161/hypertensionaha.121.17177
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发表时间：
2021-08
期刊：
影响因子：
8.3
通讯作者：
Yuhao Zhang;Sheng'an Su;Wudi Li;Yuankun Ma;Jian Shen;Yaping Wang;Yimin Shen;Jian Chen;
中科院分区：
文献类型：
--
作者：
Yuhao Zhang;Sheng'an Su;Wudi Li;Yuankun Ma;Jian Shen;Yaping Wang;Yimin Shen;Jian Chen;
补充数字内容可在正文中找到。血流动力学超负荷导致病理性心肌肥厚，是长期顽固性心力衰竭的独立危险因素。除了神经体液调节外，机械转导最近被认为是多种情况下心肌肥厚的主要调节因素。然而，目前对心肌细胞上机械力换能器的鉴定和分子特征的研究还很少。我们首次发现了Piezo1(Piezo类型机械敏感离子通道组分1)，这是一种新的机械敏感离子通道，在压力超负荷下显著上调，并在心肌细胞T管和间盘附近丰富。通过应用心脏条件性Piezo1基因敲除小鼠(Piezo1fl/flMyh6Cre+，Piezo1Cko)进行横动脉缩窄，我们证明了Piezo1在心肌肥厚的发展和随后的不利重构中是必需的。体外机械牵张或激动剂Yoda1激活Piezo1可导致体外培养的心肌细胞扩张，而Piezo1沉默或Yoda1类似物Dooku1或Piezo1抑制剂GsMTx4可阻断Piezo1的激活。从机制上讲，Piezo1通过调节细胞外钙内流和细胞内钙超载，扰乱细胞内钙稳态，从而增加钙依赖信号、钙调神经磷酸酶和钙蛋白酶的激活。抑制钙调神经磷酸酶或钙蛋白酶可阻断Yoda1诱导的心肌肥大标志物的上调和心肌细胞的肥大生长。从心脏转录组的角度来看，大多数受Piezo1影响的基因在肌肉细胞生理、紧密连接和相应的信号转导方面都高度丰富。这项研究描述了Piezo1在压力超负荷诱导的心肌肥厚中的未知作用。它可能部分破译钙在病理生理条件下的不同作用，暗示有希望成为心脏功能障碍的治疗靶点。
Supplemental Digital Content is available in the text. Hemodynamic overload induces pathological cardiac hypertrophy, which is an independent risk factor for intractable heart failure in long run. Beyond neurohumoral regulation, mechanotransduction has been recently recognized as a major regulator of cardiac hypertrophy under a myriad of conditions. However, the identification and molecular features of mechanotransducer on cardiomyocytes are largely sparse. For the first time, we identified Piezo1 (Piezo type mechanosensitive ion channel component 1), a novel mechanosensitive ion channel with preference to Ca2+ was remarkably upregulated under pressure overload and enriched near T-tubule and intercalated disc of cardiomyocyte. By applying cardiac conditional Piezo1 knockout mice (Piezo1fl/flMyh6Cre+, Piezo1Cko) undergoing transverse aortic constriction, we demonstrated that Piezo1 was required for the development of cardiac hypertrophy and subsequent adverse remodeling. Activation of Piezo1 by external mechanical stretch or agonist Yoda1 lead to the enlargement of cardiomyocytes in vitro, which was blocked by Piezo1 silencing or Yoda1 analog Dooku1 or Piezo1 inhibitor GsMTx4. Mechanistically, Piezo1 perturbed calcium homeostasis, mediating extracellular Ca2+ influx and intracellular Ca2+ overload, thereby increased the activation of Ca2+-dependent signaling, calcineurin, and calpain. Inhibition of calcineurin or calpain could abolished Yoda1 induced upregulation of hypertrophy markers and the hypertrophic growth of cardiomyocytes in vitro. From a comprehensive view of the cardiac transcriptome, most of Piezo1 affected genes were highly enriched in muscle cell physiology, tight junction, and corresponding signaling. This study characterizes an undefined role of Piezo1 in pressure overload induced cardiac hypertrophy. It may partially decipher the differential role of calcium under pathophysiological condition, implying a promising therapeutic target for cardiac dysfunction.