Piezo1通过激活Src激酶介导高压诱导心房肌细胞电重塑

Piezo1 involved in electrical remodeling in atrial myocytes induced by high hydrostatic pressure through Src kinase

目的探讨机械敏感离子通道Piezo1在高血压所致心房肌细胞电重构中的作用及可能机制。方法选取30~32周龄自发性高血压大鼠(spontaneously hypertensive rats,SHR),予缬沙坦(valsartan,Val,30 mg·kg-1·d-1)降低血压,以Wistar大鼠为对照,Western blot检测不同组别大鼠心耳组织中,以及体外给予不同压力(20或40 mmHg),Piezo1抑制剂(GsmTx4)和激动剂(Yoda1)处理下,心房肌细胞株(HL^(-1)细胞)内Piezo1,Src和Cav1.2的蛋白表达改变。全细胞膜片钳技术检测心房肌细胞的L型钙电流(L-type calcium current,ICa,L)和动作电位时程(action potential duration,APD)。结果与Wistar大鼠相比,SHR心房组织Piezo1和Src蛋白表达明显增加,Cav1.2蛋白表达明显降低(P<0.05);缬沙坦可逆转SHR心房组织中上述蛋白表达改变(P<0.05);较高静水压(40 mmHg)可使HL^(-1)细胞内的Piezo1和Src蛋白表达升高(P<0.05),伴APD缩短,ICa,L和Cav1.2蛋白的表达降低(P<0.05),GsmTx4可明显逆转上述变化。此外,Piezo1激动剂Yoda1可模拟上述压力所诱导的心房肌细胞电重构及相关信号分子的改变。结论机械敏感离子通道Piezo1参与高血压诱导电重构,与激活Src激酶信号通路导致ICa,L下降有关。

Aim To investigate the role of mechanosensitive ion channel Piezo1 in regulating electrical remodeling of atrial myocytes induced by hypertension and to further explore the potential mechanisms.Methods Spontaneously hypertensive rats(SHR)aged 30-32 weeks treated with or without valsartan(30 mg·kg-1·d-1)were used.Wistar rats were used as control.Western blot was used to detect the protein expression of Piezo1,Src and Cav1.2 in atrial appendages of rats and in atrial myocytes(HL^(-1) cells)exposed to different levels of high hydrostatic pressure(20 and 40 mmHg),Piezo1 inhibitor(GsmTx4)and agonist(Yoda1)in vitro.Whole-cell patch clamp technique was employed to detect L-type calcium current(ICa,L)and action potential duration(APD)of atrial myocytes.Results Compared with Wistar rats in control group,the protein expressions of Piezo1 and Src significantly increased and the expression of Cav1.2 decreased in SHR group(P<0.05),while the above changes could be reversed in SHR treated with valsartan(P<0.05).Meanwhile,higher hydrostatic pressure(40 mmHg)could increase the expressions of Piezo1 and Src in HL^(-1) cells(P<0.05)and decrease the protein expression of Cav1.2(P<0.05),accompanied by a shortened APD and a decreased ICa,L.GsmTx4 could significantly reverse the above changes.In addition,Piezo1 agonist Yoda1 could simulate electrical remodeling and related signal molecule changes in atrial myocytes induced by the high hydrostatic pressure.Conclusions Mechanosensitive ion channel Piezo1 participates in electrical remodeling induced by hypertension via activating Src kinase signaling pathway and then leading to the decrease of ICa,L.