Differential and reciprocal regulation between hypoxia-inducible factor-α subunits and their prolyl hydroxylases in pulmonary arteries of rat with hypoxia-induced hypertension

被引:17
作者
Chen, Yun-Rong [1 ]
Dai, Ai-Guo [1 ]
Hu, Rui-Cheng [1 ]
Jiang, Yong-Liang [1 ]
机构
[1] Hunan Province Geriatr Hosp, Human Inst Gerontol, Dept Resp Med, Changsha 410001, Peoples R China
关键词
hypoxia-inducible factor; prolyl hydroxylase; hypertension; pulmonary; hydroxylation;
D O I
10.1111/j.1745-7270.2006.00174.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Hypoxia-inducible factor (HIF)-alpha subunits (HIF-1 alpha, HIF-2 alpha and HIF-3 alpha), which play a pivotal role during the development of hypoxia-induced pulmonary hypertension (HPH), are regulated through post-translational hydroxylation by their three prolyl hydroxylase domain-containing proteins (PHD1, PHD2 and PHD3). PHDs could also be regulated by HIF. But differential and reciprocal regulation between HIF-alpha and PHDs during the development of HPH remains unclear. To investigate this problem, a rat HPH model was established. Mean pulmonary arterial pressure increased significantly after 7 d of hypoxia. Pulmonary artery remodeling index and right ventricular hypertrophy became evident after 14 d of hypoxia. HIF-1 alpha and HIF-2 alpha mRNA increased slightly after 7 d of hypoxia, but HIF-3 alpha increased significantly after 3 d of hypoxia. The protein expression levels of all three HIF-alpha were markedly upregulated after exposure to hypoxia. PHD2 mRNA and protein expression levels were upregulated after 3 d of hypoxia; PHD1 protein declined after 14 d of hypoxia without significant mRNA changes. PHD3 mRNA and protein were markedly upregulated after 3 d of hypoxia, then the mRNA remained at a high level, but the protein declined after 14 d of hypoxia. In hypoxic animals, HIF-1 alpha proteins negatively correlated with PHD2 proteins, whereas HIF-2 alpha and HIF-3 alpha proteins showed negative correlations with PHD3 and PHD1 proteins, respectively. All three HIF-alpha proteins were positively correlated with PHD2 and PHD3 mRNA. In the present study, HIF-alpha subunits and PHDs showed differential and reciprocal regulation, and this might play a key pathogenesis role in hypoxia-induced pulmonary hypertension.
引用
收藏
页码:423 / 434
页数:12
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