J. Cell. Mol. Med：杨宝峰等发现缺氧调控心肌肥厚新机制

近日，国际著名杂志《细胞与分子医学期刊》（Journal of Cellular and Molecular Medicine）发表了哈尔滨医科大学的一项研究成果，首次证实了轻度缺氧HIF-1α可以调控心肌肥厚，可望为生理性或病理性心肌肥厚的防治提供新的靶点和药物干预策略。

这篇题为《缺氧诱导因子HIF-1α激活瞬时受体TRPC通道促进轻度缺氧心肌细胞肥大》的论文是哈医大药学院青年专家初文峰教授在杨宝峰院士的指导下完成的研究成果。
 
据课题组成员初文峰教授介绍，体育锻炼人群或高原性心脏病人均可出现心肌肥厚。其中，氧浓度的变化是一种细胞生理学的基本特征，长期的慢性缺氧作为一个重要诱因参与到心肌肥厚的发生发展过程之中。而细胞内钙浓度([Ca2+]i) 的增高为诱发心肌肥厚的重要机制之一，但在缺氧条件下其增高机制尚不明确。缺氧应答中起重要作用的转录因子是缺氧诱导因子HIF-1α，在细胞缺氧时细胞内HIF-1α显著增高。如瞬时受体电位通道(TRP)，在细胞凋亡、增殖、分化过程中起重要调节作用，其亚型TRPC1，TRPC3和TRPC6在心肌细胞中存在且与心肌肥厚发生密切相关，电生理学特征为一种钙通透的非选择性阳离子通道。
 
该课题采用电生理学、影像学和分子生物学等实验技术，在证明轻度缺氧（10% O2）造成心肌细胞肥大的基础上，进一步阐明其机制与HIF-1α的表达上调，从而激活TRPC3，TRPC6通道，并导致外钙内流引起 [Ca 2+ ]i的增加，增高的[Ca2+]i继而激活参与心肌细胞肥大关键调节分子－活化T细胞核因子(NFAT)信号通路有关。
 
该研究首次证实了轻度缺氧时HIF-1α调控心肌肥厚，并为生理性或病理性心肌肥厚的防治提供新的靶点和药物干预策略，对人们如何在缺氧条件下进行科学锻炼保护心脏具有指导意义。

doi:10.1111/j.1582-4934.2011.01497.x
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Mild hypoxia induced cardiomyocyte hypertrophy via up-regulation of HIF-1α-mediated TRPC signaling

Wenfeng Chu1,?, Lin Wan1,?, Dan Zhao2,?, Xuefeng Qu1, Fulai Cai1, Rong Huo1, Ning Wang1, Jiuxin Zhu1, Chun Zhang1, Fangfang Zheng1, Ruijun Cai1, Deli Dong1, Yanjie Lu1, Baofeng Yang1,*

Hypoxia-inducible factor-1 alpha (HIF-1α) is a central transcriptional regulator of hypoxic response. The present study was designed to investigate the role of HIF-1α in mild hypoxia-induced cardiomyocytes hypertrophy and its underlying mechanism. Mild hypoxia (MH, 10% O2) caused hypertrophy in cultured neonatal rat cardiac myocytes, which was accompanied with increase of HIF-1α mRNA and accumulation of HIF-1α protein in nuclei. Transient receptor potential canonical (TRPC) channels including TRPC3 and TRPC6, except for TRPC1 were increased, and Ca2+-calcineurin signals were also enhanced in a time-dependent manner under MH condition. MH-induced cardiomyocytes hypertrophy, TRPC up-regulation and enhanced Ca2+-calcineurin signals were inhibited by a HIF-1α specific blocker, SC205346 (30 μM); whereas promoted by HIF-1α overexpression. Electrophysiological voltage-clamp demonstrated that DAG analogue, OAG (30 μM) induced TRPC current by as much as 170% in neonatal rat cardiomyocytes overexpressing HIF-1α compared to negative control. These results implicate that HIF-1α plays a key role in development of cardiac hypertrophy in responses to hypoxic stress. Its mechanism is associated with up-regulating TRPC3, TRPC6 expression, activating TRPC current and subsequently leading to enhanced Ca2+- calcineurin signals.