Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA; and.
Departments of Cell, Molecular & Developmental Biology; and.
J Cardiovasc Pharmacol. 2020 May;75(5):385-398. doi: 10.1097/FJC.0000000000000749.
Cyclic GMP (cGMP) represents a classic intracellular second messenger molecule. Over the past 2 decades, important discoveries have identified that cGMP signaling becomes deranged in heart failure (HF) and that cGMP and its main kinase effector, protein kinase G, generally oppose the biological abnormalities contributing to HF, in experimental studies. These findings have influenced the design of clinical trials of cGMP-augmenting drugs in HF patients. At present, the trial results of cGMP-augmenting therapies in HF remain mixed. As detailed in this review, strong evidence now exists that protein kinase G opposes pathologic cardiac remodeling through regulation of diverse biological processes and myocardial substrates. Potential reasons for the failures of cGMP-augmenting drugs in HF may be related to biological mechanisms opposing cGMP or because of certain features of clinical trials, all of which are discussed.
环磷酸鸟苷（cGMP）是一种经典的细胞内第二信使分子。在过去的 20 年中，重要的发现表明 cGMP 信号在心力衰竭（HF）中失调，并且 cGMP 及其主要激酶效应物蛋白激酶 G 通常与导致 HF 的生物学异常相反，这在实验研究中得到了证实。这些发现影响了 HF 患者中 cGMP 增强药物的临床试验设计。目前，HF 中 cGMP 增强疗法的试验结果仍然喜忧参半。正如本综述中详细阐述的那样，现在有强有力的证据表明，蛋白激酶 G 通过调节多种生物过程和心肌底物来对抗病理性心脏重构。cGMP 增强药物在 HF 中失败的潜在原因可能与对抗 cGMP 的生物学机制有关，也可能与临床试验的某些特征有关，所有这些都将进行讨论。
