Effects of Regulator of G Protein Signaling 19 (RGS19) on Heart Development and Function

Abstract

Wnt/Wg genes play a critical role in the development of various organisms. For example, the Wnt/␤-catenin signal promotes heart formation and cardiomyocyte differentiation in mice. Previous studies have shown that RGS19 (regulator of G protein signaling 19), which has G␣ subunits with GTPase activity, inhibits the Wnt/␤-catenin signal through inactivation of G␣ o . In the present study, the effects of RGS19 on mouse cardiac development were observed. In P19 teratocarcinoma cells with RGS19 overexpression, RGS19 inhibited cardiomyocyte differentiation by blocking the Wnt signal. Additionally, several genes targeted by Wnt were down-regulated. For the in vivo study, we generated RGS19-overexpressing transgenic (RGS19 TG) mice. In these transgenic mice, septal defects and thin-walled ventricles were observed during the embryonic phase of development, and the expression of cardiogenesis-related genes, BMP4 and Mef2C, was reduced significantly. RGS19 TG mice showed increased expression levels of brain natriuretic peptide and ␤-MHC, which are markers of heart failure, increase of cell proliferation, and electrocardiogram analysis shows abnormal ventricle repolarization. These data provide in vitro and in vivo evidence that RGS19 influenced cardiac development and had negative effects on heart function.

Regulators of G-Protein-Signaling Proteins: Negative Modulators of G-Protein-Coupled Receptor Signaling

“…This fact suggests that these mice have increased vascular tone from elevated signaling responses to angiotensin. Even though there was hypertension, there was not any cardiac hypertrophy or differences in cardiac systolic contractility that might have contributed to the elevated blood pressure in these mice (Biesemann et al, 2014;Chakir et al, 2011b;Ji et al, 2010;Jones et al, 2012;Momen et al, 2014;Sjogren et al, 2012;Takimoto et al, 2009;Tsang et al, 2010;Yue et al, 2010;Zhang et al, 2006). RGS2 knockout mice had other abnormalities that might contribute to their hypertension.…”

“…In vitro studies showed that overexpressed or reduced RGS19 inhibited cardiomyocyte differentiation by blocking the Wnt signaling pathway through inactivation of the Ga o subunit in mouse F9 embryonic teratocarcinoma cells (Feigin and Malbon, 2007;Ji et al, 2010), which might partially explain the reduced cell proliferation observed in these embryonic hearts. Few littermates of the RGS19 TG mice survived but displayed increased levels of heart failure markers, increased cell proliferation, and abnormal ventricle repolarization, indicating abnormal heart function (Ji et al, 2010).…”

“…Finally, studies in transgenic mice overexpressing RGS19 (RGS19 TG) demonstrated an important role in heart development and reported negative effects on heart function (Ji et al, 2010). Altered cell proliferation, septal defects and thin-walled ventricles were observed in embryonic hearts, which might be explained by the reduced expression of cardiogenesis-related genes found in these hearts, such as BMP4, Mef 2C, or b-catenin (Ji et al, 2010).…”

“…Altered cell proliferation, septal defects and thin-walled ventricles were observed in embryonic hearts, which might be explained by the reduced expression of cardiogenesis-related genes found in these hearts, such as BMP4, Mef 2C, or b-catenin (Ji et al, 2010).…”

“…Few littermates of the RGS19 TG mice survived but displayed increased levels of heart failure markers, increased cell proliferation, and abnormal ventricle repolarization, indicating abnormal heart function (Ji et al, 2010).…”