Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University Barry and Judy Silverman College of Pharmacy, Fort Lauderdale, FL 33328-2018, USA.
Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University Barry and Judy Silverman College of Pharmacy, Fort Lauderdale, FL 33328-2018, USA.
Biochem Pharmacol. 2023 Dec;218:115904. doi: 10.1016/j.bcp.2023.115904. Epub 2023 Nov 3.
Angiotensin II (AngII), as an octapeptide hormone normally ionized at physiological pH, cannot cross cell membranes and thus, relies on, two (mainly) G protein-coupled receptor (GPCR) types, ATR and ATR, to exert its intracellular effects in various organ systems including the cardiovascular one. Although a lot remains to be elucidated about the signaling of the ATR, ATR signaling is known to be remarkably versatile, mobilizing a variety of G protein-dependent and independent signal transduction pathways inside cells to produce a biological outcome. Cardiac ATR signaling leads to hypertrophy, adverse remodeling, fibrosis, while vascular ATR signaling raises blood pressure via vasoconstriction, but also elicits hypertrophic, vascular growth/proliferation, and pathological remodeling sets of events. In addition, adrenal ATR is the major physiological stimulus (alongside hyperkalemia) for secretion of aldosterone, a mineralocorticoid hormone that contributes to hypertension, electrolyte abnormalities, and to pathological remodeling of the failing heart. Regulator of G protein Signaling (RGS) proteins, discovered about 25 years ago as GTPase-activating proteins (GAPs) for the Gα subunits of heterotrimeric G proteins, play a central role in silencing G protein signaling from a plethora of GPCRs, including the AngII receptors. Given the importance of AngII and its receptors, but also of several RGS proteins, in cardiovascular homeostasis, the physiological and pathological significance of RGS protein-mediated modulation of cardiovascular AngII signaling comes as no surprise. In the present review, we provide an overview of the current literature on the involvement of RGS proteins in cardiovascular AngII signaling, by discussing their roles in cardiac (cardiomyocyte and cardiofibroblast), vascular (smooth muscle and endothelial cell), and adrenal (medulla and cortex) AngII signaling, separately. Along the way, we also highlight the therapeutic potential of enhancement of, or, in some cases, inhibition of each RGS protein involved in AngII signaling in each one of these cell types.
血管紧张素 II（AngII）作为一种在生理 pH 值下带正电荷的八肽激素，不能穿过细胞膜，因此依赖于两种（主要）G 蛋白偶联受体（GPCR）ATR 和 ATR，在包括心血管系统在内的各种器官系统中发挥其细胞内作用。尽管 ATR 的信号转导仍有许多有待阐明之处，但已知 ATR 信号转导非常多样化，可动员细胞内多种 G 蛋白依赖性和非依赖性信号转导途径，产生生物学效应。心脏 ATR 信号转导导致肥大、不良重塑、纤维化，而血管 ATR 信号转导通过血管收缩升高血压，但也引发肥大、血管生长/增殖和病理性重塑。此外，肾上腺 ATR 是醛固酮分泌的主要生理刺激物（与高钾血症一起），醛固酮是一种盐皮质激素，可导致高血压、电解质异常以及衰竭心脏的病理性重塑。G 蛋白信号转导调节蛋白（RGS）蛋白大约在 25 年前被发现为异三聚体 G 蛋白的 Gα亚基的 GTPase 激活蛋白（GAP），在沉默包括 AngII 受体在内的众多 GPCR 的 G 蛋白信号转导中发挥核心作用。鉴于 AngII 及其受体以及几种 RGS 蛋白在心血管稳态中的重要性，RGS 蛋白介导的心血管 AngII 信号转导调节的生理和病理意义也就不足为奇了。在本综述中，我们通过分别讨论 RGS 蛋白在心脏（心肌细胞和心肌成纤维细胞）、血管（平滑肌和内皮细胞）和肾上腺（髓质和皮质）AngII 信号转导中的作用，概述了目前关于 RGS 蛋白在心血管 AngII 信号转导中作用的文献。在此过程中，我们还强调了增强每种 RGS 蛋白在这些细胞类型中的 AngII 信号转导中的作用，或者在某些情况下抑制每种 RGS 蛋白的治疗潜力。
