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

Purpose: Protective effect of 17 beta-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% O2) for 42 and 96 h, respectively, with or without ormeloxifene pre-treatment (1 mu M). 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 17 beta-hydroxysteroid dehydrogenase (17 beta HSD) 1 & 2 expressions, reducing 17 beta-estradiol production and estrogen receptors alpha and beta in HPASMC but increasing estrone, proliferation, inflam-mation, oxidative stress, and mitochondrial dysfunction. Similarly, monocrotaline decreased plasma 17 beta-estra-diol and uterine weight in ovary-intact rats. Further, monocrotaline altered 17 beta HSD1 & 2 expressions and reduced estrogen receptors alpha and beta, 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 17 beta-estradiol synthesis. Furthermore, orme-loxifene decreased cardiac hypertrophy and right ventricular remodeling induced by hypoxia and monocrotaline.Conclusion: This study demonstrates that ormeloxifene promoted pulmonary 17 beta-estradiol synthesis, alleviated inflammation, improved the NOX4/HO1/Nrf/PPAR gamma/PGC-1 alpha axis, and attenuated pulmonary hypertension. It is evidently safe at tested concentrations and may be effectively repurposed for pulmonary hypertension treatment.

Automated summary

This study investigated the ameliorative effects of ormeloxifene, a selective estrogen receptor modulator, in pulmonary hypertension. The results showed that ormeloxifene promoted the synthesis of 17β-estradiol, alleviated inflammation, and improved the NOX4/HO1/Nrf/PPAR gamma/PGC-1 alpha axis, thereby attenuating pulmonary hypertension.