Thatcher Spencer, Khalid Arbab, Ahmed Abu-Bakr, Gill Randeep, Kia Ali
Kirk Kerkorian School of Medicine at UNLV, Las Vegas, NV 89106, USA.
Department of Internal Medicine, Kirk Kerkorian School of Medicine at UNLV, Las Vegas, NV 89106, USA.
Int J Mol Sci. 2025 Jul 1;26(13):6361. doi: 10.3390/ijms26136361.
Right heart failure (RHF) is a major cause of morbidity and mortality, often resulting from pulmonary arterial hypertension and characterized by impaired calcium (Ca) handling and maladaptive remodeling. Phosphodiesterase 9A (PDE9A), a cGMP-specific phosphodiesterase, has been proposed as a potential contributor to RHF pathogenesis by suppressing the cardioprotective cGMP-PKG signaling pathway-a conclusion largely extrapolated from left-sided heart failure models. This review examines existing evidence regarding PDE9A's role in RHF, focusing on its effects on intracellular calcium cycling, fibrosis, hypertrophy, and contractile dysfunction. Data from preclinical models demonstrate that pathological stress upregulates PDE9A expression in cardiomyocytes, leading to diminished PKG activation, impaired SERCA2a function, RyR2 instability, and increased arrhythmogenic Ca leak. Pharmacological or genetic inhibition of PDE9A restores cGMP signaling, improves calcium handling, attenuates hypertrophic and fibrotic remodeling, and enhances ventricular compliance. Early-phase clinical studies in heart failure populations suggest that PDE9A inhibitors are well tolerated and effectively augment cGMP levels, although dedicated trials in RHF are still needed. Overall, these findings indicate that targeting PDE9A may represent a promising therapeutic strategy to improve outcomes in RHF by directly addressing the molecular mechanisms underlying calcium mishandling and myocardial remodeling.
右心衰竭（RHF）是发病和死亡的主要原因，通常由肺动脉高压引起，其特征是钙（Ca）处理受损和适应性重塑不良。磷酸二酯酶9A（PDE9A）是一种特异性作用于cGMP的磷酸二酯酶，通过抑制具有心脏保护作用的cGMP-PKG信号通路，被认为是RHF发病机制的一个潜在因素——这一结论很大程度上是从左心衰竭模型推断而来的。本综述探讨了关于PDE9A在RHF中作用的现有证据，重点关注其对细胞内钙循环、纤维化、肥大和收缩功能障碍的影响。临床前模型的数据表明，病理应激会上调心肌细胞中PDE9A的表达，导致PKG激活减少、SERCA2a功能受损、RyR2不稳定以及致心律失常的钙泄漏增加。对PDE9A进行药理或基因抑制可恢复cGMP信号，改善钙处理，减轻肥大和纤维化重塑，并增强心室顺应性。心力衰竭人群的早期临床研究表明，PDE9A抑制剂耐受性良好且能有效提高cGMP水平，不过仍需要针对RHF的专门试验。总体而言，这些发现表明，通过直接解决钙处理不当和心肌重塑背后的分子机制，靶向PDE9A可能是改善RHF预后的一种有前景的治疗策略。
