[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 1alpha (HIF-1alpha) 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-1alpha mRNA expression in lung tissue was measured by in site hybridization (ISH). The protein expression of HIF-1alpha 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 P < 0.05]. 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)%, P < 0.05]. 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-1alpha 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-1alpha protein was markedly up-regulated in H(3) group (0.209 +/- 0.009, P < 0.05), reaching its peak at H(7) group (0.232 +/- 0.008, P < 0.05), then tended to decline in H(14) group and H(21) group. HIF-1alpha 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, P < 0.05), then remained stable in pulmonary arterial tunica intima. Linear correlation analysis showed that p-ERK, HIF-1alpha mRNA and mPAP were correlated with vessel morphometry and RVHI (P < 0.01); p-ERK was positively correlated with HIF-1alpha mRNA and protein (tunica intima).


CONCLUSIONS
MAPK as a signal transduction may play an important role in the development of hypoxia-induced pulmonary hypertension.
Kong
Chun-chu
CC
Department of Respiratory Medicine, Hunan Institute of Gerontology-Hunan Province Geriatric Hospital, Changsha 410001, China.
Dai
Ai-guo
AG
D000818:Animals; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism*; D000860:Hypoxia / Q000150:complications; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D020928:Mitogen-Activated Protein Kinases