Abstract 10225: The Estrogen Metabolite 16α-Hydroxyestrone Promotes Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH) is up to threefold more prevalent in women than men. Estrogen and/or its metabolites are a risk factor in PAH. In support of this, increased expression of the estrogen-metabolising enzyme cytochrome P450 1B1 (CYP1B1) is reported in experimental and human PAH. To further investigate this hypothesis, we assessed the effects of CYP1B1 and CYP1B1-derived estrogen metabolites (2-, 4- and 16-hydroxyestrogens) in PAH. Estrogen stimulated human pulmonary artery smooth muscle cell (PASMC) proliferation, as assessed via DNA synthesis and cell number, and this was inhibited via CYP1B1 inhibition. Proliferative effects of the CYP1B1-derived estrogen metabolites 2-hydroxyestrone, 2-hydroxyestradiol, 4-hydroxyestrone, 4-hydroxyestradiol, 16α-hydroxyestrone and 16α-hydroxyestradiol were assessed in PASMCs. Both 16α-hydroxyestrone and 16α-hydroxyestradiol enhanced PASMC proliferation compared to control, whilst the 2- and 4-hydroxyestrogens had no proliferative effect. In vivo, the administration of 16α-hydroxyestrone (1.5mg/kg/day for 21 days via i.p injection) resulted in the development of PAH compared to vehicle, as assessed via increased right ventricular systolic pressure (27.26 + 0.96mmHg c.f. 21.01 + 1.36mmHg; P<0.01; n=7), pulmonary vascular remodelling (14.19 + 1.65% c.f. 6.04 + 0.77%; n=5; P<0.01) and right ventricular hypertrophy (0.25 + 0.01 c.f. 0.21 + 0.01; P<0.05; n=7-8). CYP1B1 inhibition is sufficient to abolish estrogen-induced PASMC proliferation, suggesting the involvement of pro-proliferative CYP1B1-derived estrogen metabolites. Specifically, both 16α hydroxyestrone and 16α-hydroxyestradiol appear to mediate proliferation. In further support of this, 16α-hydroxyestrone promotes the development of PAH in vivo. In conclusion, our evidence suggests that females may be at increased risk to the development of PAH via effects of the CYP1B1-derived estrogen metabolites 16α-hydroxyestrone and 16α-hydroxyestradiol.
- © 2011 by American Heart Association, Inc.