Department of Medicine, Division of Cardiology, Baltimore, MD; and.
Department of Pharmacology and Molecular Sciences, Baltimore, MD.
J Cardiovasc Pharmacol. 2020 Jun;75(6):483-493. doi: 10.1097/FJC.0000000000000773.
Cyclic nucleotide phosphodiesterases comprise an 11-member superfamily yielding near 100 isoform variants that hydrolyze cAMP or cGMP to their respective 5'-monophosphate form. Each plays a role in compartmentalized cyclic nucleotide signaling, with varying selectivity for each substrate, and conveying cell and intracellular-specific localized control. This review focuses on the 5 phosphodiesterases (PDEs) expressed in the cardiac myocyte capable of hydrolyzing cGMP and that have been shown to play a role in cardiac physiological and pathological processes. PDE1, PDE2, and PDE3 catabolize cAMP as well, whereas PDE5 and PDE9 are cGMP selective. PDE3 and PDE5 are already in clinical use, the former for heart failure, and PDE1, PDE9, and PDE5 are all being actively studied for this indication in patients. Research in just the past few years has revealed many novel cardiac influences of each isoform, expanding the therapeutic potential from their selective pharmacological blockade or in some instances, activation. PDE1C inhibition was found to confer cell survival protection and enhance cardiac contractility, whereas PDE2 inhibition or activation induces beneficial effects in hypertrophied or failing hearts, respectively. PDE3 inhibition is already clinically used to treat acute decompensated heart failure, although toxicity has precluded its long-term use. However, newer approaches including isoform-specific allosteric modulation may change this. Finally, inhibition of PDE5A and PDE9A counter pathological remodeling of the heart and are both being pursued in clinical trials. Here, we discuss recent research advances in each of these PDEs, their impact on the myocardium, and cardiac therapeutic potential.
环核苷酸磷酸二酯酶由 11 个成员组成的超家族，产生近 100 种同工型变体，可将 cAMP 或 cGMP 水解为各自的 5'-单磷酸形式。每种同工酶在局部化的环核苷酸信号转导中发挥作用，对每种底物的选择性不同，并传递细胞和细胞内特定的局部控制。这篇综述重点介绍了在心肌细胞中表达的能够水解 cGMP 的 5 种磷酸二酯酶（PDEs），并已证明它们在心脏生理和病理过程中发挥作用。PDE1、PDE2 和 PDE3 也可以水解 cAMP，而 PDE5 和 PDE9 则是 cGMP 的选择性酶。PDE3 和 PDE5 已经在临床应用中，前者用于心力衰竭，而 PDE1、PDE9 和 PDE5 都在积极研究用于治疗心力衰竭。在过去的几年中，研究揭示了每种同工酶对心脏的许多新的影响，从选择性药理学阻断或在某些情况下激活方面扩大了治疗潜力。PDE1C 抑制被发现可提供细胞存活保护并增强心肌收缩力，而 PDE2 抑制或激活分别在肥大或衰竭的心脏中产生有益作用。PDE3 抑制已在临床上用于治疗急性失代偿性心力衰竭，尽管毒性使其无法长期使用。然而，包括同工酶特异性变构调节在内的新方法可能会改变这一状况。最后，抑制 PDE5A 和 PDE9A 可对抗心脏的病理性重塑，并且这两种酶都在临床试验中进行研究。在这里，我们讨论了这些 PDE 中的每一种的最新研究进展、它们对心肌的影响以及心脏治疗的潜力。
