Department of Medical Information Science, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuou-ku, Kumamoto 860-8556, Japan; Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
J Cardiol. 2021 Oct;78(4):261-268. doi: 10.1016/j.jjcc.2021.03.004. Epub 2021 Apr 2.
Cyclic guanosine monophosphate (cGMP), an intracellular second messenger molecule synthesized by guanylated cyclases (GCs), controls various myocardial properties, including cell growth and survival, interstitial fibrosis, endothelial permeability, cardiac contractility, and cardiovascular remodeling. These processes are mediated by the main cGMP effector protein kinase G (PKG) activation of which exerts intrinsic protective responses against the adverse effects of neurohormonal stimulation and pathological cardiac stress. Therapeutic strategies that enhance cGMP levels and PKG activation have been used for heart failure, which can be executed by reducing natriuretic peptide (NP) proteolysis, enhancing cGMP synthesis, or blocking cGMP hydrolysis. Among these, reducing NP clearance with neprilysin inhibitor combined with angiotensin receptor blocker has been shown to greatly improve the prognosis of patients with heart failure with reduced ejection fraction (HFrEF) compared to the prognosis of patients on standard therapy using angiotensin-converting enzyme inhibitors. Moreover, in a recent phase III clinical trial, soluble GC-derived cGMP generation was shown to have potential efficacy in the management of HFrEF. Despite the clinical significance of cGMP/PKG signaling activated by either soluble or particulate GCs in heart failure, the differential signaling events downstream of intracellular cGMP, which are precisely controlled not only by PKG activation but also by the changes in its targeting and compartmentalization depending on the pathophysiology of heart disease, are not yet completely understood. Hitherto, the importance of the latter PKG regulatory mechanisms in developing therapeutic strategies has not been elucidated. Further investigation of redox-based PKG modulation will aid in the successful development of clinical therapies and could also lead to the establishment of improved personalized treatments for patients with heart failure.
环鸟苷酸（cGMP）是一种由鸟苷酸环化酶（GCs）合成的细胞内第二信使分子，可控制多种心肌特性，包括细胞生长和存活、间质纤维化、内皮通透性、心脏收缩力和心血管重塑。这些过程是由 cGMP 主要效应蛋白蛋白激酶 G（PKG）的激活介导的，PKG 的激活对神经激素刺激和病理性心脏应激的不良影响产生内在的保护反应。增强 cGMP 水平和 PKG 激活的治疗策略已用于心力衰竭，可通过减少利钠肽（NP）的蛋白水解、增强 cGMP 合成或阻断 cGMP 水解来实现。在这些策略中，与使用血管紧张素转换酶抑制剂的标准治疗相比，用 Neprilysin 抑制剂联合血管紧张素受体阻断剂减少 NP 清除，已显示出极大地改善射血分数降低的心力衰竭（HFrEF）患者的预后。此外，最近的 III 期临床试验表明，可溶性 GC 衍生的 cGMP 生成在 HFrEF 的管理中具有潜在疗效。尽管心力衰竭中可溶性或颗粒 GC 激活的 cGMP/PKG 信号具有临床意义，但细胞内 cGMP 下游的差异信号事件，不仅受到 PKG 激活的精确控制，而且还受到其靶向和区室化的变化的精确控制，这些变化不仅取决于心脏病的病理生理学，目前尚不完全清楚。迄今为止，后者 PKG 调节机制在开发治疗策略中的重要性尚未阐明。进一步研究基于氧化还原的 PKG 调节将有助于成功开发临床疗法，并可能导致为心力衰竭患者建立改进的个性化治疗方法。
