Protective mechanism of SIRT1 on Hcy-induced atrial fibrosis mediated by TRPC3
Protective mechanism of SIRT1 on Hcy-induced atrial fibrosis mediated by TRPC3
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SIRT1对TRPC3介导的Hcy诱导心房纤维化的保护机制
DOI：
10.1111/jcmm.14757
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发表时间：
2019-11-04
影响因子：
5.3
通讯作者：
Li, Juxiang
中科院分区：
文献类型：
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作者：
Han, Lu;Tang, Yanhua;Li, Juxiang
高血浆同型半胱氨酸（Hcy）水平被认为是心房颤动（AF）的危险因素，与心房纤维化的病理后果密切相关，可导致心力衰竭，死亡率高；本研究表明，在Hcy刺激下，典型瞬时受体电位3 （TRPC3）通道和sirtuin 1型（SIRT1）之间的关系介导了心房纤维化。从窦性心律（SR）或房颤患者中获取左心房附件，用于评估Hcy浓度与TRPC3和SIRT1介导的心脏纤维化的潜在机制之间的关系。接下来，我们在小鼠身上进行了主动脉横缩术（TAC）来研究两者之间的关系。通过co-IP、BLI和慢病毒转染实验探讨心房纤维化与TRPC3和SIRT1蛋白相关的机制。qPCR和WB分别检测基因和蛋白的表达。在高Hcy饮食的HH小鼠组中观察到更高水平的心房纤维化。这些结果表明，房颤患者可能更容易发生心房纤维化，并有很高的可能性发展为高同型半胱氨酸血症。此外，我们的研究结果与TRPC3通道上调导致胶原异常积累的假设一致，SIRT1下调是高Hcy的一个病因因素，而高Hcy反过来又易发生心房纤维化，大大增加了房颤的可能性。
High plasma levels of homocysteine (Hcy) are regarded as a risk factor for atrial fibrillation (AF), which is closely associated with the pathological consequence of atrial fibrosis and can lead to heart failure with a high mortality rate; here, we show that atrial fibrosis is mediated by the relationship between canonical transient receptor potential 3 (TRPC3) channels and sirtuin type 1 (SIRT1) under the stimulation of Hcy. The left atrial appendage was obtained from patients with either sinus rhythm (SR) or AF and used to evaluate the relationship between the concentration of Hcy and a potential mechanism of cardiac fibrosis mediated by TRPC3 and SIRT1. We next performed transverse aortic constriction (TAC) in mouse to investigate the relationship. The mechanisms underlying atrial fibrosis involving TRPC3 and SIRT1 proteins were explored by co-IP, BLI and lentivirus transfection experiments. qPCR and WB were performed to analyse gene and protein expression, respectively. The higher level of atrial fibrosis was observed in the HH mouse group with a high Hcy diet. Such results suggest that AF patients may be more susceptible to atrial fibrosis and possess a high probability of progressing to hyperhomocysteinemia. Moreover, our findings are consistent with the hypothesis that TRPC3 channel up-regulation leads to abnormal accumulation of collagen, with the down-regulation of SIRT1 as an aetiological factor of high Hcy, which in turn predisposes to atrial fibrosis and strongly enhances the possibility of AF.