Yu Ze-Yan, Gong Hutao, Kesteven Scott, Guo Yang, Wu Jianxin, Li Jinyuan Vero, Cheng Delfine, Zhou Zijing, Iismaa Siiri E, Kaidonis Xenia, Graham Robert M, Cox Charles D, Feneley Michael P, Martinac Boris
Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia.
Cardiac Physiology and Transplantation Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia.
Nat Cardiovasc Res. 2022 Jun;1(6):577-591. doi: 10.1038/s44161-022-00082-0. Epub 2022 Jun 13.
Pressure overload-induced cardiac hypertrophy is a maladaptive response with poor outcomes and limited treatment options. The transient receptor potential melastatin 4 (TRPM4) ion channel is key to activation of a Ca/calmodulin-dependent kinase II (CaMKII)-reliant hypertrophic signaling pathway after pressure overload, but TRPM4 is neither stretch-activated nor Ca-permeable. Here we show that Piezo1, which is both stretch-activated and Ca-permeable, is the mechanosensor that transduces increased myocardial forces into the chemical signal that initiates hypertrophic signaling via a close physical interaction with TRPM4. Cardiomyocyte-specific deletion of Piezo1 in adult mice prevented activation of CaMKII and inhibited the hypertrophic response: residual hypertrophy was associated with calcineurin activation in the absence of its usual inhibition by activated CaMKII. Piezo1 deletion prevented upregulation of the sodium-calcium exchanger and changes in other Ca handling proteins after pressure overload. These findings establish Piezo1 as the cardiomyocyte mechanosensor that instigates the maladaptive hypertrophic response to pressure overload, and as a potential therapeutic target.
压力超负荷诱导的心肌肥大是一种适应性不良的反应，预后较差且治疗选择有限。瞬时受体电位香草酸亚型4（TRPM4）离子通道是压力超负荷后激活依赖于钙/钙调蛋白依赖性激酶II（CaMKII）的肥大信号通路的关键，但TRPM4既不是牵张激活的，也不是钙通透的。在这里，我们表明，既是牵张激活又是钙通透的Piezo1是一种机械传感器，它通过与TRPM4紧密的物理相互作用，将增加的心肌力转化为启动肥大信号的化学信号。成年小鼠心肌细胞特异性缺失Piezo1可防止CaMKII激活并抑制肥大反应：残余肥大与钙调神经磷酸酶激活有关，而在正常情况下，激活的CaMKII会抑制钙调神经磷酸酶。Piezo1缺失可防止压力超负荷后钠钙交换体的上调以及其他钙处理蛋白的变化。这些发现确立了Piezo1作为心肌细胞机械传感器的地位，它引发了对压力超负荷的适应性不良肥大反应，并且是一个潜在的治疗靶点。
