血管紧张素II(AngII),作为八肽激素,通常在生理pH下电离,不能穿过细胞膜,因此,依靠,两种(主要)G蛋白偶联受体(GPCR)类型,AT1R和AT2R,在包括心血管在内的各种器官系统中发挥其细胞内作用。尽管关于AT2R的信号传导还有很多有待阐明,已知AT1R信号是非常通用的,在细胞内动员多种G蛋白依赖性和非依赖性信号转导途径以产生生物学结果。心脏AT1R信号导致肥大,不良重塑,纤维化,而血管AT1R信号通过血管收缩升高血压,但也会引起肥大,血管生长/增殖,和病理性重塑事件集。此外,肾上腺AT1R是醛固酮分泌的主要生理刺激(与高钾血症一起),一种导致高血压的盐皮质激素,电解质异常,以及衰竭心脏的病理性重塑。G蛋白信号调节因子(RGS)蛋白,大约25年前发现的GTP酶激活蛋白(GAP)用于异源三聚体G蛋白的Gα亚基,在沉默来自大量GPCRs的G蛋白信号中发挥核心作用,包括AngII受体.鉴于AngII及其受体的重要性,还有几种RGS蛋白,在心血管稳态中,RGS蛋白介导的心血管AngII信号调节的生理和病理意义并不令人惊讶。在本次审查中,我们提供了关于RGS蛋白参与心血管AngII信号传导的现有文献的概述,通过讨论它们在心脏(心肌细胞和心脏成纤维细胞)中的作用,血管(平滑肌和内皮细胞),和肾上腺(髓质和皮质)AngII信号,分开。一路上,我们还强调了增强的治疗潜力,或者,在某些情况下,在这些细胞类型中的每一种中抑制参与AngII信号传导的每种RGS蛋白。
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, AT1R and AT2R, 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 AT2R, AT1R 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 AT1R signaling leads to hypertrophy, adverse remodeling, fibrosis, while vascular AT1R signaling raises blood pressure via vasoconstriction, but also elicits hypertrophic, vascular growth/proliferation, and pathological remodeling sets of events. In addition, adrenal AT1R 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.