[Mitogen-activated protein kinase regulated hypoxia-inducible factor 1alpha in hypoxia-induced pulmonary hypertension in rats].

Objective To investigate the dynamic expression of hypoxia-inducible factor 1α(HIF-1α) and mitogen-activated protein kinase(MAPK) in pulmonary arteries of rats with hypoxia-induced pulmonary hypertension. Methods Forty male adult Wistar rats were randomly divided into five groups:a control group(C group) and groups with hypoxia for 3,7,14 and 21 days(H 3,H 7,H 14 and H 21 group),eight rats per group. Mean pulmonary pressure(mPAP),right ventrical hypertrophy index(RVHI) and vessel morphometry were measured. The levels of HIF-1α mRNA expression in lung tissue was measured by in site hybridization(ISH). The protein expression of HIF-1α and p-ERK,p-JNK,p-P38 were observed by immunohistochemistry or Western blot. Results The level of mPAP[(23.5±1.8)mm Hg],the ratio of vascular wall thickness to external diameter[WT,(45.5±3.1)%] and the ratio of vascular wall area to the total area[LA,(54.7±3.2)%] were significantly higher in H 7 group than those in C group[(16.2±2.0)mm Hg,(36.8±2.5)% and (63.2±2.5)% respectively,all P0.05]. These parameters reached a high level and remained stable on H 14 group,RVHI was significantly higher[(26.9±1.3)%] on H 14 group than in C group[(23.0±1.5)%,P0.05]. Expression of p-ERK protein in C group was barely positive,but was up-regulated in pulmonary arterial tunica intima and tunica media of all hypoxia rats. Expression of p-JNK and p-P38 in C group and hypoxia groups were barely positive. Expression of HIF-1α protein in C group was barely positive,but was up-regulated in pulmonary arterial tunica intima of all hypoxic rats. In pulmonary arterial tunica media,the levels of HIF-1α protein was markedly up-regulated in H 3 group(0.209±0.009, P0.05),reaching its peak at H 7 group(0.232±0.008,P0.05),then tended to decline in H 14 group and H 21 group. HIF-1α mRNA staining was barely positive in C group,H 3 group and H 7 group,but began to increase significantly at H 14 group(0.305±0.104,P0.05),then remained stable in pulmonary arterial tunica intima. Linear correlation analysis showed that p-ERK,HIF-1α mRNA and mPAP were correlated with vessel morphometry and RVHI(P0.01);p-ERK was positively correlated with HIF-1α mRNA and protein(tunica intima). Conclusion MAPK as a signal transduction may play an important role in the development of hypoxia-induced pulmonary hypertension. 14 relationanalysisshow