Differential and Reciprocal Regulation between Hypoxia-inducible Factor-αSubunits and Their Prolyl Hydroxylases in Pulmonary Arteries of Rat with Hypoxia-induced Hypertension  

作　　者：Yun-Rong CHEN Ai-Guo DAI Rui-Cheng HU Yong-Liang JIANG 

机构地区：[1]Department of Respiratory Medicine, Hunan Institute of Gerontology, Hunan Province Geriatric Hospital, Changsha 410001, China

出　　处：《Acta Biochimica et Biophysica Sinica》2006年第6期423-434,共12页生物化学与生物物理学报（英文版）

基　　金：the grants from the National Natural Science Foundation of China （No. 30570815 , 30270581）; the Hunan Province Natural Science Foundation of China （No. 05JJ30073）; the Major Science and Technology Foundation of the Ministry of Education of China （No. 03091） ; the Postdoctorate Science Foundation of China （No. 2003033436）

摘　　要：Hypoxia-inducible factor （HIF）-α subunits （HIF-1α, HIF-2α and HIF-3α）, which play a pivotal role during the development of hypoxia-induced pulmonary hypertension （HPH）, are regulated through posttranslational hydroxylation by their three prolyl hydroxylase domain-containing proteins （PHD 1, PHD2 and PHD 3 ）. PHDs could also be regulated by HIF. But differential and reciprocal regulation between HIF-α 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-1α and HIF-2α mRNA increased slightly after 7 d of hypoxia, but HIF-3α increased significantly after 3 d of hypoxia. The protein expression levels of all three HIF-α were markedly upregulated after exposure to hypoxia. PHD2 mRNA and protein expression levels were upregulated after 3 d of hypoxia; PHD 1 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-1α proteins negatively correlated with PHD2 proteins, whereas HIF-2α and HIF-3α proteins showed negative correlations with PHD3 and PHD1 proteins, respectively. All three HIF-α proteins were positively correlated with PHD2 and PHD3 mRNA. In the present study, HIF-α subunits and PHDs showed differential and reciprocal regulation, and this might play a key pathogenesis role in hypoxia-induced pulmonary hypertension.Hypoxia-inducible factor （HIF）-α subunits （HIF-1α, HIF-2α and HIF-3α）, which play a pivotal role during the development of hypoxia-induced pulmonary hypertension （HPH）, are regulated through posttranslational hydroxylation by their three prolyl hydroxylase domain-containing proteins （PHD 1, PHD2 and PHD 3 ）. PHDs could also be regulated by HIF. But differential and reciprocal regulation between HIF-α 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-1α and HIF-2α mRNA increased slightly after 7 d of hypoxia, but HIF-3α increased significantly after 3 d of hypoxia. The protein expression levels of all three HIF-α were markedly upregulated after exposure to hypoxia. PHD2 mRNA and protein expression levels were upregulated after 3 d of hypoxia; PHD 1 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-1α proteins negatively correlated with PHD2 proteins, whereas HIF-2α and HIF-3α proteins showed negative correlations with PHD3 and PHD1 proteins, respectively. All three HIF-α proteins were positively correlated with PHD2 and PHD3 mRNA. In the present study, HIF-α subunits and PHDs showed differential and reciprocal regulation, and this might play a key pathogenesis role in hypoxia-induced pulmonary hypertension.

关 键 词：hypoxia-inducible factor prolyl hydroxylase HYPERTENSION PULMONARY HYDROXYLATION 

分 类 号：R657.34[医药卫生—外科学]