title: Mild hypoxia-induced cardiomyocyte hypertrophy via up-regulation of HIF-1α-mediated TRPC signalling.
abstract: 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% O(2)) 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 Ca(2+)-calcineurin signals were also enhanced in a time-dependent manner under MH condition. MH-induced cardiomyocytes hypertrophy, TRPC up-regulation and enhanced Ca(2+)-calcineurin signals were inhibited by an 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 Ca(2+)-calcineurin signals.
authors: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China.
authors: Wenfeng
authors: W
authors: Chu
authors: Lin
authors: L
authors: Wan
authors: Dan
authors: D
authors: Zhao
authors: Xuefeng
authors: X
authors: Qu
authors: Fulai
authors: F
authors: Cai
authors: Rong
authors: R
authors: Huo
authors: Ning
authors: N
authors: Wang
authors: Jiuxin
authors: J
authors: Zhu
authors: Chun
authors: C
authors: Zhang
authors: Fangfang
authors: F
authors: Zheng
authors: Ruijun
authors: R
authors: Cai
authors: Deli
authors: D
authors: Dong
authors: Yanjie
authors: Y
authors: Lu
authors: Baofeng
authors: B
authors: Yang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics / Q000473:pathology; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003001:Cloning, Molecular; D005455:Fluorescent Antibody Technique; D006801:Humans; D006984:Hypertrophy; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics*; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; C492145:Trpc6 protein, rat; D019703:Calcineurin