Myocardial Phosphodiesterases and Their Role in cGMP Regulation.
Myocardial Phosphodiesterases and Their Role in cGMP Regulation.
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DOI：
10.1097/fjc.0000000000000773
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发表时间：
2020-06
影响因子：
3
通讯作者：
Kass DA
中科院分区：
文献类型：
--
作者：
Dunkerly-Eyring B;Kass DA
环核苷酸磷酸二酯酶包含11个成员的超家族，产生近100种同种型变体，其将cAMP或cGMP水解成它们各自的5 '-单磷酸形式。每一个都在区室化的环核苷酸信号传导中发挥作用，对每种底物具有不同的选择性，并传递细胞和细胞内特异性局部控制。本文综述了5种在心肌细胞中表达的能够水解cGMP的PDE，它们在心脏的生理和病理过程中发挥着重要作用。PDE 1、PDE 2和PDE 3也分解代谢cAMP，而PDE 5和PDE 9是cGMP选择性的。PDE 3和PDE 5已经在临床上使用，前者用于心力衰竭，而PDE 1、PDE 9和PDE 5都正在积极研究用于患者的该适应症。过去几年的研究揭示了每种亚型的许多新的心脏影响，扩大了其选择性药理学阻断或在某些情况下激活的治疗潜力。发现PDE 1C抑制可赋予细胞存活保护并增强心脏收缩力，而PDE 2抑制或激活分别在肥大或衰竭心脏中诱导有益作用。PDE 3抑制剂已经在临床上用于治疗急性失代偿性心力衰竭，尽管毒性已经排除了其长期使用。然而，新的方法，包括异构体特异性变构调节可能会改变这一点。最后，抑制PDE 5A和PDE 9A对抗心脏的病理性重塑，并且两者都在临床试验中进行。在这里，我们讨论了这些PDE的最新研究进展，它们对心肌的影响，以及心脏治疗潜力。
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 five 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, while PDE2 inhibition or activation induces beneficial effects in hypertrophied or failing hearts, respectively. PDE3 inhibition is already clinically employed to treat acute decompensated heart failure, though toxicity has precluded its long-term use. However, newer approaches including isoform specific allosteric modulation may change this. Lastly, 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.