Abstract 10227: Cytochrome P450 1B1 Promotes the Development of Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH) is characterised by elevations in pulmonary arterial pressures, arising from pulmonary vascular remodelling and vasoconstriction. The incidence of idiopathic and heritable PAH is up to three-fold higher in women than men. Estrogen is one risk factor in PAH. Previously, we identified a critical role for 17β estradiol in the development of PAH in mice over-expressing the serotonin transporter (SERT+ mice). A mutation in the gene encoding for the estrogen-metabolising enzyme cytochrome P450 1B1 (CYP1B1) is associated with the increased incidence of human PAH. Furthermore, CYP1B1 protein expression is increased in both experimental and human PAH. CYP1B1 metabolizes 17β estradiol to the 2-, 4- and 16-hydroxyestrogens. Here, we investigate the hypothesis that CYP1B1 promotes the development of PAH by assessment of hypoxia-induced PAH in mice deficient of CYP1B1 (CYP1B1-/- mice). PAH was assessed via measurement of right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH) and pulmonary vascular remodelling (PVR). WT littermate mice were studied as controls. Following exposure to chronic hypoxia, male CYP1B1-/- mice show a reduction in RVSP (n=6-9; 27.32 ± 2.05mmHg c.f. 33.84 ± 1.34mmHg, P<0.01) and PVR (n=4-5; 15.07 ± 1.49%, c.f. 22.80 ± 2.23%), whilst both male and female CYP1B1-/- mice exhibit reductions in RVH (n=9-11; 0.23 ± 0.01 c.f. 0.28 ± 0.01 (P<0.001) and 0.25 ± 0.01 c.f. 0.30 ± 0.01 (P<0.01), respectively). Male and female CYP1B1-/- mice also exhibit reduced pulmonary arterial vasoconstriction to serotonin, as assessed by wire myography (n=3-7; Rmax 139.8 ± 8.90, P<0.001 c.f. 314.9 ± 20.25; 222.3 ± 13.01 c.f. 291.2 ± 30.31 P<0.05, respectively). In conclusion, our findings suggest that increased 17β estradiol metabolism via CYP1B1 may be critical to PAH pathogenesis and that manipulation of CYP1B1 is be a promising therapeutic target in the treatment of PAH.
- © 2011 by American Heart Association, Inc.