Ormeloxifene, a selective estrogen receptor modulator, protects against pulmonary hypertension.

Purpose: Protective effect of 17β-estradiol is well-known in pulmonary hypertension. However, estrogen-based therapy may potentially increase the risk of breast cancer, necessitating a search for novel drugs. This study, therefore, investigated the ameliorative effects of a selective estrogen receptor modulator, ormeloxifene, in pulmonary hypertension.

Methods: Cardiomyocytes (H9C2) and human pulmonary arterial smooth muscle cells (HPASMCs) were exposed to hypoxia (1% O) for 42 and 96 h, respectively, with or without ormeloxifene pre-treatment (1 μM). Also, female (ovary-intact or ovariectomized) and male Sprague-Dawley rats received monocrotaline (60 mg/kg, once, subcutaneously), with or without ormeloxifene treatment (2.5 mg/kg, orally) for four weeks.

Results: Hypoxia dysregulated 17β-hydroxysteroid dehydrogenase (17βHSD) 1 & 2 expressions, reducing 17β-estradiol production and estrogen receptors α and β in HPASMC but increasing estrone, proliferation, inflammation, oxidative stress, and mitochondrial dysfunction. Similarly, monocrotaline decreased plasma 17β-estradiol and uterine weight in ovary-intact rats. Further, monocrotaline altered 17βHSD1 & 2 expressions and reduced estrogen receptors α and β, increasing right ventricular pressure, proliferation, inflammation, oxidative stress, endothelial dysfunction, mitochondrial dysfunction, and vascular remodeling in female and male rats, with worsened conditions in ovariectomized rats. Ormeloxifene was less uterotrophic; however, it attenuated both hypoxia and monocrotaline effects by improving pulmonary 17β-estradiol synthesis. Furthermore, ormeloxifene decreased cardiac hypertrophy and right ventricular remodeling induced by hypoxia and monocrotaline.

Conclusion: This study demonstrates that ormeloxifene promoted pulmonary 17β-estradiol synthesis, alleviated inflammation, improved the NOX4/HO1/Nrf/PPARγ/PGC-1α axis, and attenuated pulmonary hypertension. It is evidently safe at tested concentrations and may be effectively repurposed for pulmonary hypertension treatment.