Synergistic Therapeutic Effects of 2-Methoxyestradiol With Either Sildenafil or Bosentan on Amelioration of Monocrotaline-induced Pulmonary Hypertension and Vascular Remodeling

Abstract

2-Methoxyestradiol (2ME) is a major nonestrogenic metabolite of estradiol. Our previous studies suggest that 2ME, in several models of cardiac and/or vascular injury, strongly inhibits cardiac and vascular remodeling. Furthermore, our most recent study shows that in male rats, 2ME attenuates the development and retards the progression of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH), and in female rats, 2ME eliminates the exacerbation of PAH and the increased mortality due to ovariectomy. The current standard of care of patients with PAH includes treatment with an endothelin receptor antagonist (eg, bosentan) or a phosphodiesterase5 inhibitor (eg, sildenafil). Moreover, combination therapy is often prescribed. Therefore, in the present study, we compared the efficacy of 2ME (10 μg · kg(-1) · h(-1), 2ME-10) to the effects of bosentan (200 mg/kg; BOS), sildenafil (50 mg/kg; SIL), and their respective combinations with 2ME-10 (2ME + BOS and 2ME + SIL groups, respectively). Treatments were initiated 12 days after administration of MCT (60 mg/kg). Twenty-eight days after MCT administration, right ventricular peak systolic pressure was measured and morphometric analysis was conducted. 2ME exhibited beneficial effects in pulmonary hypertensive animals and had efficacy comparable to that of BOS and SIL. Importantly, combination treatments had favorable effects on survival, vascular remodeling, and inflammatory response, and the 2ME + SIL combination was significantly more efficacious than any other treatment. These results indicate that 2ME is effective in experimental PAH and suggests that 2ME may provide additional therapeutic benefit over existing drugs used for the treatment of pulmonary hypertension.

Gender, Sex Hormones and Pulmonary Hypertension

“…[130131] Furthermore, 2-ME attenuates the development and retards the progression of hypoxia-induced PH in male rats[132] and has synergistic effects with sildenafil and bosentan in attenuating pulmonary vascular remodeling and pulmonary inflammation and in reducing mortality in MCT-PH male rats. [133] Similar effects in male rats with MCT-PH are seen with synthetic analog 2-EE. [127] The beneficial effects of E2 in MCT-PH are associated with increased lung NO and prostacyclin levels and reduced endothelin levels, and the inhibitory effects on of E2 on vascular remodeling are linked to down-regulated expression of phosphorylated Akt and up-regulated expression of cyclooxygenase-2.…”

Estrogen Receptor Subtypes Mediate Distinct Microvascular Dilation and Reduction in [Ca2+]i in Mesenteric Microvessels of Female Rat

“…Studying ER subtypes and post-ER relaxation mechanisms at different stages of the estrous and menstrual cycles could help elucidate the pathogenesis of female vasospastic disorders. Also, E2 metabolites and ER agonists may be beneficial in pulmonary hypertension (Tofovic et al, 2010) and occlusive artery diseases.…”

Sex differences in the pulmonary circulation: implications for pulmonary hypertension

“…Its therapeutic potential in pulmonary vascular disease has been investigated in MCT-induced PH in rats (127,128). Treatment with 2ME was found to provide a reduction in disease progression (126). However, so far, 2ME levels have not been compared in patients with and without PAH.…”