Abstract 266: Phosphodiesterase 9A Deficiency Does Not Attenuate Chronic-hypoxic Pulmonary Hypertension

Abstract

Background: Phosphodiesterase (PDE) inhibition is a cornerstone of therapy for pulmonary arterial hypertension. A novel role for PDE9A in natriuretic peptide-mediated left ventricular cyclic guanosine monophosphate (cGMP) signaling and remodeling has recently been described. Since cGMP-signaling can promote vaso-relaxation and prevent vascular smooth muscle cell proliferation and cardiac myocyte hypertrophy, we hypothesized that PDE9A deficiency would attenuate right ventricular (RV) and pulmonary vascular remodeling during chronic RV pressure overload. Methods: Chronic-hypoxic pulmonary hypertension (CH-PH) was induced in mice lacking PDE9A expression ( Pde9a -/- ) and wild-type littermates ( Pde9a +/+ ) by exposure to normobaric hypoxia (FiO2 = 10%) for 3 weeks. RV systolic pressures were measured to quantify PH, and RV hypertrophy was quantified as the ratio of RV free wall mass to LV/septal mass (RV/LV+S). Heart, lung, and serum were flash frozen for biochemical analyses. Results: In wild-type mice, exposure to chronic hypoxia resulted in significant increases in RV pressure (30 ± 2.4 vs. 20 ± 3.2 mm Hg; P = 0.0006) and RV hypertrophy (0.34 ± 0.04 vs. 0.25 ± 0.02; P < 0.0001). Serum ANP levels were increased 5-fold with CH-PH ( P = <0.0001), associated with a 72% reduction in lung Npr3 receptor expression (responsible for ANP clearance; P < 0.0001) but no increase in RV Nppa expression. After 3 weeks of CH-PH, tissue levels of cGMP were not increased in lung (993 ± 502 pg/mg vs. 667 ± 210 pg/mg; P = 0.27) or RV (47 ± 18 pg/mg vs. 49 ± 13 pg/mg; P = 0.88) homogenates. Accordingly, serine-239 phosphorylation of vasodilatory-stimulated phosphoprotein (VASP; a surrogate for protein kinase G activation) was not increased by CH-PH in lung or RV. Expression of Pde9a RNA was not increased by CH-PH in lung or RV. Pde9a -/- mice did not have attenuated CH-PH induced increases in RVH ( P = 0.27, 2-way ANOVA) or RVSP ( P = 0.23, 2-way ANOVA) when compared to Pde9a +/+ mice. In both Pde9a -/- and Pde9a +/+ mice, CH-PH was associated with significant increases in lung PDE5A expression. Conclusions: In a murine model of chronic RV pressure overload, PDE9A deficiency does not attenuate RV remodeling or PH, despite robust increases in circulating natriuretic peptide levels.