Division of Pulmonary and Critical Care Medicine Pulmonary, Johns Hopkins University, Baltimore, Maryland, USA.
Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Physiol Rep. 2021 Sep;9(18):e15057. doi: 10.14814/phy2.15057.
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.
抑制环鸟苷酸单磷酸（cGMP）特异性磷酸二酯酶（PDE）是肺动脉高压（PAH）特异性治疗的基石。PDE9A 在心脏和肺组织中表达，是所有已知 PDE 中对 cGMP 亲和力最高的。PDE9A 缺乏通过增加利钠肽（NP）依赖性 cGMP 信号来保护小鼠免受慢性左心室（LV）压力超负荷的影响。慢性低氧性肺动脉高压（CH-PH）是慢性右心室（RV）压力超负荷的模型，先前的研究表明 NP 在小鼠模型中具有保护作用。因此，我们假设 PDE9A 缺乏会促进 NP 依赖性 cGMP 信号，并防止 CH-PH 模型中的 RV 重塑，类似于 LV 中的发现。我们使野生型和 PDE9A 缺乏型（Pde9a）C57BL/6 小鼠暴露于 CH-PH 3 周。我们测量了 CH-PH 后 RV 压力、肥大以及肺和 RV cGMP、PDE9A、PDE5A 和蛋白激酶 G 底物 VASP（血管扩张刺激磷酸蛋白）磷酸化的水平。在野生型小鼠中，CH-PH 与循环 ANP 和肺 PDE5A 的增加有关，但 cGMP、PDE9A 或 VASP 磷酸化没有增加。与 Pde9a 同窝仔鼠相比，暴露于 CH-PH 的 Pde9a 小鼠中的 cGMP 下游效应物没有增加，CH-PH 诱导的 RV 压力和肥大增加在敲除小鼠中没有减弱。综上所述，这些发现表明 PDE9A 在小鼠 CH-PH 模型中没有突出作用。
