Ormeloxifene alleviates pulmonary hypertension in monocrotaline-treated male Sprague-Dawley rats

Modulation of estrogen receptors is a promising target for novel treatment of pulmonary hypertension (PH). We have previously reported the anti-pulmonary hypertensive efficacy of ormeloxifene in female Sprague-Dawley rats; however, males present more severe phenotypic features of PH. Therefore, the protective effect of ormeloxifene was investigated in male rats to confirm its efficacy in the treatment of PH. Fifteen male Sprague-Dawley rats (220 - 250 g) were randomly assigned 3 groups (n = 5/ per group) vis-à-vis: the vehicle-treated (2 % DMSO) control group, the monocrotaline-treated (60 mg/kg, subcutaneous single injection) group, and the monocrotaline-treated ormeloxifene (2.5 mg/kg, p.o) group for 35 days. Our data show that neither monocrotaline nor ormeloxifene affected body weight, estrogen receptor (ER) α, and 17β-hydroxysteroid dehydrogenase 2 (17βHSD2). However, monocrotaline elevated right ventricular weight, decreased pulmonary ERβ and 17βHSD1 expressions, increasing right ventricular pressure. Further, monocrotaline-induced PH caused right ventricular hypertrophy (RVH) via increased inflammation, proliferation, apoptosis resistance, and vascular remodeling. In contrast, ormeloxifene improved ERβ and 17βHSD1 expressions, attenuated PH and inhibiting right ventricular hypertrophy. Our study concludes that ormeloxifene is protective against PH and RVH in males. Hence, its protective effects, probably associated with ERβ and 17βHSD1 upregulations, should be harnessed for better PH treatment.