title: Oestradiol ameliorates monocrotaline pulmonary hypertension via NO, prostacyclin and endothelin-1 pathways.
abstract: Pulmonary hypertension continues to be a serious clinical problem with high mortality. As oestrogen is a potential vasodilator of the pulmonary circulation, this study examined the mechanisms by which 17β-oestradiol improves monocrotaline (MCT)-induced pulmonary hypertension. Female Sprague-Dawley rats underwent bilateral ovariectomy or sham operations. The rats received MCT (50 mg·kg(-1)) and were treated with 17β-oestradiol (1 mg·kg(-1) per day) for either 5 weeks or only from week 4 to week 5. Plasma 17β-oestradiol concentrations were decreased in sham-operated, MCT-treated rats when compared with sham-operated rats (17.7 ± 4.7 versus 50.3 ± 15.4 pg·mL(-1); p=0.029). The 17β-oestradiol anabolic enzyme cytochrome P450 (CYP)-19 was decreased by MCT treatment, while the catabolic enzymes CYP-1A1 and -1B1 were increased. Ovariectomised and MCT-treated rats had more severe pulmonary hypertension. 17β-oestradiol suppressed pulmonary arterial smooth muscle cell proliferation and macrophage infiltration, and enhanced apoptosis by increasing nitric oxide (NO) and prostacyclin (prostaglandin (PG)I2) levels and reducing endothelin (ET)-1 levels. Phosphoinositide-3-kinase (PI3K) and Akt phosphorylations were markedly increased, but were inhibited by 17β-oestradiol treatment in rats with pulmonary hypertension. Oestrogen deficiency may aggravate development of pulmonary hypertension. 17β-oestradiol improved pulmonary hypertension via activation of the PI3K/Akt pathway to regulate NO, PGI2 and ET-1 expression.
authors.affiliation: Dept of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yuan
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Wu
authors.forename: Lan
authors.initials: L
authors.lastname: Gao
authors.forename: Ze-Qi
authors.initials: ZQ
authors.lastname: Zheng
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.forename: Han-Ying
authors.initials: HY
authors.lastname: Mei
authors.forename: Zhuo-Li
authors.initials: ZL
authors.lastname: Zhang
authors.forename: Zhi-Cheng
authors.initials: ZC
authors.lastname: Jing
mesh_terms: D000818:Animals; D001141:Aromatase / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D019332:Endothelin-1 / Q000378:metabolism*; D011464:Epoprostenol / Q000378:metabolism*; D004958:Estradiol / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use*; D005260:Female; D006439:Hemodynamics; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy*; D016686:Monocrotaline / Q000009:adverse effects; D009569:Nitric Oxide / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: D019332:Endothelin-1; D009569:Nitric Oxide; D004958:Estradiol; D016686:Monocrotaline; D011464:Epoprostenol; D001141:Aromatase; D001189:Aryl Hydrocarbon Hydroxylases; C585499:Cyp1b1 protein, rat; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D019869:Phosphatidylinositol 3-Kinases