Abstract
Inhibition of cyclic guanosine monophosphate (cGMP)‐specific phosphodiesterases (PDEs) is a cornerstone of pulmonary arterial hypertension (PAH)‐specific therapy. PDE9A, expressed in the heart and lung tissue, has the highest affinity for cGMP of all known PDEs. PDE9A deficiency protects mice against chronic left ventricular (LV) pressure overload via increased natriuretic peptide (NP)‐dependent cGMP signaling. Chronic‐hypoxic pulmonary hypertension (CH‐PH) is a model of chronic right ventricular (RV) pressure overload, and previous studies have demonstrated a protective role for NPs in the murine model. Therefore, we hypothesized that PDE9A deficiency would promote NP‐dependent cGMP signaling and prevent RV remodeling in the CH‐PH model, analogous to findings in the LV. We exposed wild‐type and PDE9A‐deficient (Pde9a −/−) C57BL/6 mice to CH‐PH for 3 weeks. We measured RV pressure, hypertrophy, and levels of lung and RV cGMP, PDE9A, PDE5A, and phosphorylation of the protein kinase G substrate VASP (vasodilatory‐stimulated phosphoprotein) after CH‐PH. In wild‐type mice, CH‐PH was associated with increased circulating ANP and lung PDE5A, but no increase in cGMP, PDE9A, or VASP phosphorylation. Downstream effectors of cGMP were not increased in Pde9a −/− mice exposed to CH‐PH compared with Pde9a +/+ littermates, and CH‐PH induced increases in RV pressure and hypertrophy were not attenuated in knockout mice. Taken together, these findings argue against a prominent role for PDE9A in the murine CH‐PH model.
Highlights
Inhibiting specific phosphodiesterase (PDE) enzymes to augment cyclic guanosine monophosphate-dependent signaling is a cornerstone of therapy in pulmonary arterial hypertension (PAH) (Archer & Michelakis, 2009)
Atrial natriuretic peptide (ANP) overexpression is protective in the mouse model of chronic hypoxic pulmonary hypertension (CH- PH) (Klinger et al, 1993), while ANP knockout mice develop more severe chronic hypoxia (CH)-P H (Chen et al, 2006; Klinger et al, 1999; Sun et al, 2000)
We showed that Chronic-hypoxic pulmonary hypertension (CH-PH) is associated with increased serum ANP levels but not increased cyclic guanosine monophosphate (cGMP)- dependent signaling in right ventricular (RV) or lung homogenates
Summary
Inhibiting specific phosphodiesterase (PDE) enzymes to augment cyclic guanosine monophosphate (cGMP)-dependent signaling is a cornerstone of therapy in pulmonary arterial hypertension (PAH) (Archer & Michelakis, 2009). | 2 of 10 and myocardial contractility, while preventing hypertrophy and proliferation. These beneficial effects are primarily mediated via cGMP-dependent protein kinase (PKG) (Hofmann et al, 2009), while concurrent activation of PDE isoforms can hydrolyze cGMP and effectively downregulate the signal (Omori & Kotera, 2007). Myocardial PDE9A is upregulated in left heart failure, and PDE9A-deficient mice had less myocyte hypertrophy and better myocardial function than PDE9A-expressing mice in a model of chronic left ventricular (LV) pressure overload (Lee et al, 2015). The beneficial effects of PDE9A deficiency in this model were mediated through augmentation of natriuretic peptide (NP)-dependent cGMP signaling. We hypothesized that PDE9A deficiency would promote NP-dependent cGMP signaling and attenuate CH-PH
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