[Transforming growth factor beta1 correlates inducible nitric oxide synthase in pulmonary arteries of rats with hypoxia-induced pulmonary hypertension].
OBJECTIVE
To investigate the dynamic expression of transforming growth factor beta(1)(TGF-beta(1)) and inducible nitric oxide synthase (iNOS) in pulmonary arteries of rats with hypoxia-induced pulmonary hypertension (HPH).


METHODS
Forty adult male 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), H(21) group), eight rats per group. Mean pulmonary arterial pressure (mPAP), vessel morphometry and right ventricle hypertrophy index (RVHI) were measured. Lungs were inflation fixed for in situ hybridization and immunohistochemistry.


RESULTS
mPAP increased significantly in H(7) group [(18.41 +/- 0.37) mm Hg, 1 mm Hg = 0.133 kPa, P < 0.05], reaching its peak in H(14) group [(21.17 +/- 0.23) mm Hg], then remained at the high level. Hypoxia induced pulmonary artery remodeling and right ventricle hypertrophy index became evident in H(14) group. Expression of iNOS protein in control group (0.109 +/- 0.021) was weakly positive in pulmonary arterial tunica media, while the level of iNOS protein was markedly up-regulated in H(3) group (0.225 +/- 0.030, P < 0.01), reaching its peak in H(7) group (0.312 +/- 0.036), then remained at the high level. Expression of iNOS mRNA in C group (0.112 +/- 0.030) was weakly positive in pulmonary arterial wall, while the level of iNOS mRNA was markedly up-regulated in H(3) group (0.245 +/- 0.036), reaching its peak in H(7) group (0.318 +/- 0.034, P < 0.01), then remained at the high level. Expression of TGF-beta(1) protein in C group (0.042 +/- 0.012) was weakly positive, but the level of TGF-beta(1) protein was markedly up-regulated in H(3) group (0.198 +/- 0.031), reaching its peak in H(7) group (0.267 +/- 0.035, P < 0.01), and then tended to decline in H(14) and H(21) group. TGF-beta(1) mRNA staining was weakly positive in C group (0.145 +/- 0.018), H(3) group (0.163 +/- 0.021) and H(7) group (0.176 +/- 0.026), but began to increase significantly in H(14) group (0.385 +/- 0.028, P < 0.01), and then remained stable. TGF-beta(1) protein and mRNA were located predominantly in tunica adventitia and tunica media. Linear correlation analysis showed that TGF-beta(1) mRNA, iNOS mRNA and protein were positively correlated with mPAP, vessel morphometry and RVHI (r = 0.843 - 0.937, all P < 0.01). TGF-beta(1) protein (tunica adventitia) was negatively correlated with iNOS mRNA and protein (r = -0.856, -0.835, all P < 0.01).


CONCLUSIONS
Interaction of TGF-beta(1) and iNOS plays a role in the pathogenesis of HPH in rats. iNOS can regulate the expression of TGF-beta(1) gene by NO. TGF-beta(1) can regulate the expression of iNOS gene by decreased stability and translation of iNOS mRNA and increased degradation of iNOS protein.
Jiang
Yong-liang
YL
Department of Respiratory Medicine, Hunan Institute of Gerontology, Hunan Province Geriatric Hospital, Changsha 410001, China.
Dai
Ai-guo
AG
Li
Qi-fang
QF
Hu
Rui-cheng
RC
D000818:Animals; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism*; D000860:Hypoxia / Q000150:complications; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D015854:Up-Regulation
D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat