Abstract 981: Hypoxia Results in Exacerbation of Pulmonary Arterial Hypertension (PAH) in Male Mice with Deletion of PPARγin Smooth Muscle Cells (SMC) but Females are Protected by Adiponectin Mediated Induction of PPARα

Abstract

Lung tissues of patients with PAH have reduced levels of the peroxisome proliferator activated receptor gamma (PPARγ) and we previously reported that transgenic male mice with deletion of PPARγ in arterial smooth muscle (SM22CrePPARγ flox/flox ) develop spontaneous PAH. Moreover, PPARγ is necessary in mediating bone morphogenetic protein (BMP-2) inhibition of PDGF-BB induced SMC proliferation. We therefore hypothesized that PAH would be exacerbated in SM22CrePPARγ flox/flox mice under conditions like chronic hypoxia (3 weeks, FiO 2 =0.10) that induce PDGF-BB mediated SMC proliferation. Results: Consistent with this hypothesis, we report a more severe PAH phenotype only in the male SM22CrePPARγ flox/flox mice, as measured by greater right ventricular systolic pressure (RVSP: 38.6 vs. 30.9 mmHg), right ventricular hypertrophy (RVH=right ventricle/left ventricle+septum: 0.58 vs 0.35), and arterial muscularization (90.6 vs 60.3 %), when compared to littermate controls (p<0.05, n=6 – 8 per group, for all comparisons). Interestingly, female SM22CrePPARγ flox/flox mice were resistant to spontaneous or chronic hypoxia-induced PAH (RVSP: 18.5mmHg). We investigated the acute hypoxic vasoconstrictive response and found it exaggerated in the male but suppressed in the female (RVSP: 43.12 vs 20.42mmHg) SM22CrePPARγ flox/flox mice. We found no reduction in endothelin-1 (P<0.05) in the female vs. male SM22CrePPARγ flox/flox mice but serum levels of adiponectin were twofold higher (14.5 vs 6.9 μg/ml; p<0. 001) in females under normoxia and hypoxia. We further show through cell counts, that in pulmonary artery (PA) SMC from male SM22CrePPARγ flox/flox mice, BMP2 fails to suppress PA SMC proliferation in response to PDGF-BB (p<0.01; n=3) but exogenous adiponectin can ‘rescue’ this phenotype (p<0.01, n=3). The mechanism appears to be related to adiponectin mediated induction of PPAR alpha (PPARγ mRNA relative level: 0.37 vs 0.42 after adiponectin pretreatment, p<0.01), which we report for the first time in PA SMC. Conclusion : These findings strengthen the potential efficacy of PPAR-α/ γ agonists in the treatment of PAH patients with low endogenous levels of PPAR-γ and/or adiponectin, such as those with BMP-RII dysfunction or insulin resistance.