Study on the role of receptor-activated cation channel TRPC3 in cardiac remodeling

慢性高血压或缺血引起的心脏结构重构是心功能不全的主要原因。我们以前曾报道过，二酰基甘油激活的瞬时受体电位经典通道（TRPC 3和TRPC 6）介导的压力超负荷诱导的心肌肥厚体内。我们在这里关注TRPC 6通道活性受Thr 69磷酸化负调控的事实，并发现PDE或心房利钠肽的抑制通过TRPC 6抑制来抑制心脏肥大和高血压。值得注意的是，TRPC 6蛋白在血管平滑肌细胞中与PKA和PDE 3形成蛋白质信号传导复合物。此外，TRPC 3依赖于TRPC 3介导的Ca 2+内流与蛋白激酶C相互作用，导致通过激活NADPH氧化酶产生活性氧，导致心脏重塑的发展，如肥大和纤维化。这些结果有力地表明TRPC 3/6蛋白信号复合物的形成在心脏重构中起着关键作用。

Structural remodeling of the heart induced by chronic hypertension or ischemia is a major cause for cardiac dysfunction. We have previously reported that diacylglycerol-activated transient receptor potential canonical channels(TRPC3 and TRPC6) mediate pressure overload-induced cardiac hypertrophy invivo. We here focused on the fact that TRPC6 channel activities are negatively regulated by Thr69 phosphorylation, and found that inhibition of PDEs or atrial natriuretic peptide suppresses cardiac hypertrophy and hypertension through TRPC6 inhibition. Notably, TRPC6 proteins formed a protein signaling complex with PKA and PDE3 in vascular smooth muscle cells. Furthermore, TRPC3 interacts with protein kinase C dependently on TRPC3-mediated Ca2+ influx, leading to production of reactive oxygen species via activation of NADPH oxidase, resulting in development of cardiac remodeling, such as hypertrophy and fibrosis. These results strongly suggest that formation of TRPC3/6 protein signaling complex plays a pivotal role in cardiac remodeling.