G protein regulation by RGS proteins in the pathophysiology of dilated cardiomyopathy

Abstract

Regulators of G protein signaling (RGS) proteins fine-tune signaling via heterotrimeric G proteins to maintain physiologic homeostasis in various organ systems of the human body including the brain, kidney, heart, and vasculature. Impaired regulation of G protein signaling by RGS proteins is implicated in the pathogenesis of several human diseases including various forms of cardiomyopathy such as hypertrophic cardiomyopathy and dilated cardiomyopathy (DCM). Both genetic and nongenetic changes that impinge on G protein signaling in cardiomyocytes are implicated in the etiology of DCM, and there is accumulating evidence that such genetic and nongenetic changes affecting G protein signaling in cell types other than cardiomyocytes could serve as a DCM trigger in humans. This review discusses and highlights mammalian RGS proteins and their roles in cardiac physiology and disease, with a specific focus on the current understanding of the etiology of DCM and the pathogenic roles of RGS proteins that are prominently expressed in the cardiovascular system. Growing evidence suggests that defects in G protein regulation by RGS proteins in the cardiovascular system likely contribute to cardiomyocyte structural damage and decreased contractile function that hallmark DCM. Further studies that enhance the understanding of the dynamics of G protein regulation by RGS proteins in several cell types in the myocardium and the vasculature are critical to gaining more insight into the etiology of DCM and heart failure, and to the identification of novel therapeutic targets.

Keywords: G protein signaling; RGS proteins; dilated cardiomyopathy; pathological mechanisms; vascular dysfunction.

Figure 1.

Potential mechanisms by which changes in the expression or function of RGS proteins could lead to defects in signaling pathways that are key to maintaining normal cardiomyocyte structure and function. Studies involving animal models of RGS gene knockout or overexpression have been implicated in the pathogenesis of DCM hallmarks, including left ventricular dilation, cardiomyocyte damage, and ventricular arrhythmia. Thus, exogenous stressors and factors that impinge on the expression or steady-state levels of RGS proteins could contribute to DCM pathogenesis. ai, inhibitory G protein α subunit; α_q, G_q/11 class G protein α subunit; α_s, stimulatory G protein α subunit; βγ, G protein β and γ subunits; AC, adenylyl cyclase; AKT, protein kinase B; Ca²⁺, calcium ion; cAMP, 3′,5′-cyclic adenosine monophosphate; DAG, diacylglycerol; DCM, dilated cardiomyopathy; GPCR, G protein-coupled receptor; stimulatory G protein α subunit; GTP, guanosine triphosphate; IP₃, inositol 1,4,5-trisphosphate; PDK1, 3-phosphoinositide-dependent kinase 1; PI3K, phosphoinositide 3-kinase; PIP₂, phosphatidylinositol 4,5-bisphosphate; PKC, protein kinase C; PLC, phospholipase C; RGS, regulator of G protein signaling; Rx, RGS × family; SR, sarcoplasmic reticulum. Figure created with a licensed version of BioRender.com.

Figure 2.

Contribution of vascular dysfunction to DCM pathogenesis. Certain mutations in cardiomyocytes implicated in DCM pathogenesis are also found in cells of the coronary microcirculation. Vascular dysfunction resulting from such mutations and environmental stressors, including chronic alcohol use and certain medications, are associated with decreased coronary vasodilatory reserve and increased oxidative and nitrosative stress and decline in oxygen and nutrient delivery to the myocardium that together can contribute to cardiomyocyte damage and dysfunction. α_s, stimulatory G protein α subunit; AC, adenylyl cyclase; ATP, adenosine triphosphate; cAMP, 3′,5′-cyclic adenosine monophosphate; Ca²⁺, calcium ion; DAG, diacylglycerol; DCM, dilated cardiomyopathy; Gα_q, G_q/11 class G protein α subunit; GPCR, G protein-coupled receptor; IP₃, inositol 1,4,5-trisphosphate; LMNA, human laminin A/C gene; NO, nitric oxide; O₂, molecular oxygen; ONOO⁻, peroxynitrite; PIP₂, phosphatidylinositol 4,5-bisphosphate; PKC, protein kinase C; PLC, phospholipase C; ROS, reactive oxygen species. Figure created with a licensed version of BioRender.com.