William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
J Cardiovasc Pharmacol. 2020 May;75(5):370-384. doi: 10.1097/FJC.0000000000000724.
Heart failure (HF) is a common consequence of several cardiovascular diseases and is understood as a vicious cycle of cardiac and hemodynamic decline. The current inventory of treatments either alleviates the pathophysiological features (eg, cardiac dysfunction, neurohumoral activation, and ventricular remodeling) and/or targets any underlying pathologies (eg, hypertension and myocardial infarction). Yet, since these do not provide a cure, the morbidity and mortality associated with HF remains high. Therefore, the disease constitutes an unmet medical need, and novel therapies are desperately needed. Cyclic guanosine-3',5'-monophosphate (cGMP), synthesized by nitric oxide (NO)- and natriuretic peptide (NP)-responsive guanylyl cyclase (GC) enzymes, exerts numerous protective effects on cardiac contractility, hypertrophy, fibrosis, and apoptosis. Impaired cGMP signaling, which can occur after GC deactivation and the upregulation of cyclic nucleotide-hydrolyzing phosphodiesterases (PDEs), promotes cardiac dysfunction. In this study, we review the role that NO/cGMP and NP/cGMP signaling plays in HF. After considering disease etiology, the physiological effects of cGMP in the heart are discussed. We then assess the evidence from preclinical models and patients that compromised cGMP signaling contributes to the HF phenotype. Finally, the potential of pharmacologically harnessing cardioprotective cGMP to rectify the present paucity of effective HF treatments is examined.
心力衰竭（HF）是多种心血管疾病的常见后果，被理解为心脏和血液动力学下降的恶性循环。目前的治疗方法要么缓解病理生理特征（例如，心脏功能障碍、神经激素激活和心室重构），要么针对任何潜在的病理（例如，高血压和心肌梗死）。然而，由于这些方法不能治愈疾病，HF 相关的发病率和死亡率仍然很高。因此，该疾病构成了未满足的医疗需求，迫切需要新的治疗方法。环鸟苷酸-3'，5'-单磷酸（cGMP）由一氧化氮（NO）和利钠肽（NP）反应性鸟苷酸环化酶（GC）酶合成，对心脏收缩力、肥大、纤维化和细胞凋亡发挥多种保护作用。GC 失活和环核苷酸水解磷酸二酯酶（PDEs）上调后，cGMP 信号转导受损，导致心脏功能障碍。在本研究中，我们综述了 NO/cGMP 和 NP/cGMP 信号在 HF 中的作用。在考虑疾病病因后，讨论了 cGMP 在心脏中的生理作用。然后，我们评估了临床前模型和患者的证据，表明受损的 cGMP 信号转导导致 HF 表型。最后，检查了利用心脏保护性 cGMP 来纠正目前 HF 治疗效果不佳的潜力。
