phytoestrogens and Hypertension--Pulmonary

Pulmonary arterial hypertension is characterized by high pulmonary blood pressure, vascular remodeling and right ventricular hypertrophy. In the present study, we investigated whether genistein would prevent the development of low temperature-induced pulmonary hypertension in broilers. Hemodynamic parameters, vascular remodeling, the expression of endothelial nitric oxide and endothelin-1 content in lung tissue were evaluated. The results demonstrated that genistein significantly reduced pulmonary arterial hypertension and suppressed pulmonary arterial vascular remodeling without affecting broilers' performance. The beneficial effects appeared to be mediated by restoring endothelial function especially endothelial nitric oxide and endothelin-1, two critical vasoactive molecules that associated with the development of hypertension. Genistein supplementation might be a potential therapeutic strategy for the treatment of pulmonary hypertension.

Topics: Animals; Ascites; Chickens; Cold Temperature; Cyclic GMP; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Genistein; Hemodynamics; Hypertension, Pulmonary; Lung; Male; Neovascularization, Pathologic; Nitric Oxide Synthase Type III; Pericardial Effusion; Phytoestrogens; Poultry Diseases; Weight Gain

Phytoestrogen genistein may be useful to treat pulmonary arterial hypertension (PAH). However, its mechanism is still not clear. The aim of the present study was to confirm the therapeutic effects of phytoestrogen genistein on PAH in monocrotaline-induced rat model and to explore its mechanism.. Sprague-Dawley male rats were randomly divided into 4 groups: control group (n=8), PAH group (n=8), genistein treament group with three different doses (n=8 in each dose group) and group of PI3K inhibitor LY294002. The rat model of PAH was induced by monocrotaline (MCT). The situation of survival of rats was observed. Pathological studies of lung and heart tissues were performed. Western-blot detection of P-Akt and P-eNOS expression levels in lung tissue was carried out. Nitrate reductase analysis was used to measure nitric oxide (NO) in lung tissue.. Genistein treatment resulted in significant improvement in the speed of tricuspid regurgitation, diameter of pulmonary artery, mean pulmonary artery pressure and right ventricular hypertrophy index. Genistein treatment also resulted in significant improvement in the stenosis of pulmonary artery, proliferation of smooth muscle, right ventricular hypertrophy and myocardial hypertrophy. These therapeutic effects were more obvious with increasing dose of genistein. After genistein treatment, amelioration in survival rates of PAH rats was observed. PI3K inhibitor LY294002 could block these therapeutic effects. In rat lung tissue, P-Akt, P-eNOS and NO expressions were increased significantly in genistein treatment group when compared with PAH group (p<0.05, respectively). The increase in expression level of P-Akt, P-eNOS and NO was correlated with genistein dose. P-Akt, P-eNOS and NO expressions in lung tissue increased slightly in the PI3K inhibitor LY294002 group when compared with PAH group, but the difference was not statistically significant (p>0.05).. We confirmed that genistein could relax pulmonary vascular resistance, reduce pulmonary artery pressure, improve right heart function and ameliorate survival rate in the rat model of PAH. Our study suggested that its mechanism was related with PI3K/Akt/eNOS signal pathway. Phytoestrogen genistein may become a new and effective drug for patients with PAH.

Topics: Animals; Blotting, Western; Disease Models, Animal; Genistein; Heart Ventricles; Hypertension, Pulmonary; Lung; Male; Monocrotaline; Nitric Oxide Synthase Type III; Phosphatidylinositol 3-Kinases; Phytoestrogens; Proto-Oncogene Proteins c-akt; Random Allocation; Rats; Rats, Sprague-Dawley; Signal Transduction

Pretreatment with a phytoestrogen genistein has been shown to attenuate the development of pulmonary hypertension (PH). Because PH is not always diagnosed early, we examined whether genistein could also reverse preexisting established PH and prevent associated right heart failure (RHF). PH was induced in male rats by 60 mg/kg of monocrotaline. After 21 days, when PH was well established, rats received daily injection of genistein (1 mg/kg per day) for 10 days or were left untreated to develop RHF by day 30. Effects of genistein on human pulmonary artery smooth muscle cell and endothelial cell proliferation and neonatal rat ventricular myocyte hypertrophy were assessed in vitro. Severe PH was evident 21 days after monocrotaline, as peak systolic right ventricular pressure increased to 66.35±1.03 mm Hg and right ventricular ejection fraction reduced to 41.99±1.27%. PH progressed to RHF by day 30 (right ventricular pressure, 72.41±1.87 mm Hg; RV ejection fraction, 29.25±0.88%), and mortality was ≈75% in RHF rats. Genistein therapy resulted in significant improvement in lung and heart function as right ventricular pressure was significantly reduced to 43.34±4.08 mm Hg and right ventricular ejection fraction was fully restored to 65.67±1.08% similar to control. Genistein reversed PH-induced pulmonary vascular remodeling in vivo and inhibited human pulmonary artery smooth muscle cell proliferation by ≈50% in vitro likely through estrogen receptor-β. Genistein also reversed right ventricular hypertrophy (right ventricular hypertrophy index, 0.35±0.029 versus 0.70±0.080 in RHF), inhibited neonatal rat ventricular myocyte hypertrophy, and restored PH-induced loss of capillaries in the right ventricle. These improvements in cardiopulmonary function and structure resulted in 100% survival by day 30. Genistein restored PH-induced downregulation of estrogen receptor-β expression in the right ventricle and lung. In conclusion, genistein therapy not only rescues preexisting severe PH but also prevents the progression of severe PH to RHF.

Topics: Animals; Capillaries; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Estrogen Receptor beta; Genistein; Glycine max; Heart Failure; Humans; Hypertension, Pulmonary; In Vitro Techniques; Male; Phytoestrogens; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Treatment Outcome

Phytoestrogens derived from soybeans reverse endothelial dysfunction in a number of animal models of systemic vascular disease. Based on these studies, we hypothesized that phytoestrogens would reverse chronic hypoxia-induced endothelial dysfunction in rat pulmonary arteries. To test this hypothesis we examined the effect of genistein, the major phytoestrogen found in soybeans, on carbachol-induced relaxation in phenylephrine-constricted pulmonary artery rings isolated from normoxic rats and rats exposed to 14 days of hypobaric hypoxia. Compared with that in normoxic rats, the response to carbachol was impaired in pulmonary arteries isolated from rats exposed to chronic hypoxia. In normoxic rat pulmonary arteries, genistein (30 microM) did not change the maximum relaxation to carbachol. In contrast, genistein significantly enhanced the relaxation response to carbachol in pulmonary arteries from hypoxic rats, restoring it to the levels seen in normoxic rats. 17beta-estradiol (10 microM) and daidzein (30 microM), a structural analog of genistein lacking inhibitory effects on tyrosine kinases, also restored the relaxation response to carbachol in hypoxic rat pulmonary arteries. The nitric-oxide synthase inhibitor N(omega)-nitro-L-arginine (100 microM) completely blocked the genistein, daidzein, and 17beta-estradiol-induced restoration of the relaxation response to carbachol, whereas the estrogen receptor antagonist ICI 182,780 (10 microM) had no effect on the relaxation responses. We conclude that the phytoestrogens genistein and daidzein act like estrogen in restoring nitric oxide-mediated relaxation in chronically hypoxic rat pulmonary arteries and that this effect does not appear to be mediated by inhibition of tyrosine kinases or by known estrogen receptors.

Topics: Animals; Carbachol; Cholinergic Agonists; Chronic Disease; Dose-Response Relationship, Drug; Estradiol; Estrogen Antagonists; Estrogens, Non-Steroidal; Fulvestrant; Genistein; Hypertension, Pulmonary; Hypoxia; In Vitro Techniques; Isoflavones; Male; Nitric Oxide; Nitric Oxide Synthase; Phytoestrogens; Plant Preparations; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents