Regulator of G-Protein Signaling 10 Negatively Regulates Cardiac Remodeling by Blocking Mitogen-Activated Protein Kinase–Extracellular Signal-Regulated Protein Kinase 1/2 Signaling

Abstract

Regulator of G-protein signaling 10 (RGS10) is an important member of the RGS family and produces biological effects in multiple organs. We used a genetic approach to study the role of RGS10 in the regulation of pathological cardiac hypertrophy and found that RGS10 can negatively influence pressure overload–induced cardiac remodeling. RGS10 expression was markedly decreased in failing human hearts and hypertrophic murine hearts. The extent of aortic banding–induced cardiac hypertrophy, dysfunction, and fibrosis in RGS10-knockout mice was exacerbated, whereas the heart of transgenic mice with cardiac-specific RGS10 overexpression exhibited an alleviated response to pressure overload. Consistently, RGS10 also inhibited an angiotensin II–induced hypertrophic response in isolated cardiomyocytes. Mechanistically, cardiac remodeling improvement elicited by RGS10 was associated with the abrogation of mitogen-activated protein kinase kinase 1/2–extracellular signal-regulated protein kinase 1/2 signaling. Furthermore, the inhibition of mitogen-activated protein kinase kinase–extracellular signal-regulated protein kinase 1/2 transduction abolished RGS10 deletion-induced hypertrophic aggravation. These findings place RGS10 and its downstream signaling mitogen-activated protein kinase kinase–extracellular signal-regulated protein kinase 1/2 as crucial regulators of pathological cardiac hypertrophy after pressure overload and identify this pathway as a potential therapeutic target to attenuate the pressure overload–driven cardiac remodeling.

Regulators of G-Protein Signaling 10 and Heart Failure

“…In summary, Miao et al 4 have clearly demonstrated a critical role of RGS10 in heart disease, and pharmacological approaches aimed at enhancing RGS10 action may show salutary therapeutic effects. …”

“…Miao et al studied the novel role of RGS10 in heart failure by using 2 mutant murine models, RGS10 overexpression and knockout (KO), and showed RGS10-mediated regulation of Gαq/11 plays a crucial role in the maintenance of heart function. 4 Signal transduction through the activation of GPCRs is a dominant mechanism for the regulation of cardiovascular physiology, including the regulation of heart rate, myocardial hypertrophy, and contractility, and vascular tone. The success of pharmaceuticals that inhibit β-adrenergic receptors and AT1 receptors, which represent stereotypical GPCRs, also demonstrate the importance of these signaling pathways in disease pathogenesis.…”

“…They used transgenic mice with RGS10 overexpression in cardiomyocytes and RGS10KO to elucidate the role of RGS10 in pressure-overload heart failure using the surgical aortic banded model. 4 Generation of RGS10KO mice by Miao et al was accomplished by CRISPRCas9 technology, a precise and efficient genome editing tool that identifies any DNA sequence by a programmable single guide RNA, which has become a popular approach in genetic engineering. 4,12 As used in this study, this technology created a basic germline knockout of RGS10, meaning that RGS10…”

“…Therefore, understanding the mechanism for RGS10 reduction in disease models may lead to a therapeutic target for intervention and is an important question raised by this study. 4 Tumor necrosis factor-α downregulates RGS10 mRNA and protein levels in neuronal cells; overexpression of RGS10 activated the cyclic adenosine monophosphate (cAMP) response element-binding protein and protected the cells from tumor necrosis factor-α-induced damage.…”

Pivotal Role of Regulator of G-protein Signaling 12 in Pathological Cardiac Hypertrophy

“…Among them, RGS3, RGS5, and RGS10 protect against pressure overload-induced hypertrophic response and improve cardiac function by inhibiting MEK1/2-ERK1/2 signaling. 11,13,14 RGS12 is the largest, typical multidomain member of the RGS family. 15 In addition to a central RGS domain, RGS12 contains a PDZ (PSD-95/ discslarge/ZO-1 homology) domain, with putative CXCR2-binding properties, and a phosphotyrosine-binding domain at the N terminus, whereas a tandem repeat of Ras-binding domains and a Gai/o-Loco motif are located at the C terminus of RGS12.…”