Genistein, a phytoestrogen, attenuates monocrotaline-induced pulmonary hypertension.
BACKGROUND
Pulmonary hypertension is characterized by high pulmonary blood pressure, vascular remodeling, and right ventricular hypertrophy. Although recent studies suggest that an imbalance between endothelial mediators on pulmonary vasculature may contribute to the development of pulmonary hypertension, the pathogenesis is not fully understood and the treatment of pulmonary hypertension is still unresolved.


OBJECTIVE
The purpose of this study was to investigate whether genistein, a phytoestrogen derived from soybean, would prevent the development of monocrotaline (MCT)-induced pulmonary hypertension in rats. Hemodynamic parameters of catheterized rats and morphological feature of lungs were evaluated among MCT-treated rats receiving or not receiving genistein. Furthermore, examination of expression in endothelial nitric oxide synthase and endothelin-1 peptide level was performed.


METHODS
Daily supplementation with either genistein (0.2 mg/kg) or vehicle was started 2 days prior to a single-dose injection of MCT (60 mg/kg). On day 28, rats underwent catheterization, and right ventricular hypertrophy and morphological features were assessed. Furthermore, endothelial nitric oxide synthase and endothelin-1 were examined by Western blot analysis and radioimmunoassay, respectively, in homogenated lungs.


RESULTS
In rats that received daily supplementation of genistein, mean pulmonary arterial pressure was significantly reduced, whereas mean systemic arterial pressure and heart rate were unaltered compared with MCT control rats on day 28 after MCT injection. Right ventricular hypertrophy, medial wall thickness of pulmonary arteries corresponding to the terminal bronchioles, and the degree of neo-muscularization of more distal arteries were less severe in genistein-treated rats. Genistein supplementation improved MCT-induced downregulation of expression of endothelial nitric oxide synthase in the lungs. However, endothelin-1 peptide levels did not differ among all groups of lungs.


CONCLUSIONS
We conclude that daily supplementation of genistein potently attenuates MCT-induced pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular remodeling in rats. The underlying mechanism responsible for this effect may be partly related to the restoration of a decreased expression of endothelial nitric oxide synthase.
Homma
Noriyuki
N
Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo, Japan.
Morio
Yoshiteru
Y
Takahashi
Hideki
H
Yamamoto
Akihito
A
Suzuki
Tsutomu
T
Sato
Koichi
K
Muramatsu
Masashi
M
Fukuchi
Yoshinosuke
Y
D000818:Animals; D015153:Blotting, Western; D015536:Down-Regulation / Q000187:drug effects; D019332:Endothelin-1 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D019833:Genistein / Q000494:pharmacology* / Q000627:therapeutic use*; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000517:prevention & control; D007150:Immunohistochemistry; D008168:Lung / Q000378:metabolism; D008297:Male; D016686:Monocrotaline / Q000009:adverse effects; D019001:Nitric Oxide Synthase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014655:Vascular Resistance / Q000187:drug effects
D019332:Endothelin-1; D004791:Enzyme Inhibitors; D016686:Monocrotaline; D019833:Genistein; D019001:Nitric Oxide Synthase