Differential and reciprocal regulation between hypoxia-inducible factor-alpha subunits and their prolyl hydroxylases in pulmonary arteries of rat with hypoxia-induced hypertension.
Hypoxia-inducible factor (HIF)-alpha subunits (HIF-1alpha, HIF-2alpha and HIF-3alpha), 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-1alpha and HIF-2alpha mRNA increased slightly after 7 d of hypoxia, but HIF-3alpha 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-1alpha proteins negatively correlated with PHD2 proteins, whereas HIF-2alpha and HIF-3alpha 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.
Chen
Yun-Rong
YR
Department of Respiratory Medicine, Hunan Institute of Gerontology, Hunan Province Geriatric Hospital, Changsha 410001, China.
Dai
Ai-Guo
AG
Hu
Rui-Cheng
RC
Jiang
Yong-Liang
YL
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D015971:Gene Expression Regulation, Enzymologic; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry*; D017403:In Situ Hybridization; D008168:Lung / Q000473:pathology; D011393:Procollagen-Proline Dioxygenase / Q000737:chemistry*; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014157:Transcription Factors / Q000737:chemistry*; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011393:Procollagen-Proline Dioxygenase; D012333:RNA, Messenger; D014157:Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C497444:Hif1a protein, rat; C424683:Hif3a protein, rat