Dual loss of RGS2 and RGS5 decreases cardiomyocyte contractility and causes arrhythmia in adult mice

Cardiomyocyte contractility is essential to maintaining proper cardiac output and blood flow throughout the circulatory system. This action is dependent upon proper G protein-coupled receptor (GPCR) signaling. Previous studies showed G-protein dysregulation due to the loss of regulator of G protein signaling (RGS) 2 and 5, separately, impairs cardiac structure and function, including hypertrophy and arrhythmia. RGS2 and 5 are GTPase activating proteins (GAPs) that accelerate the hydrolysis of GTP by G proteins, resulting in a rapid signaling termination. We examined how the dual absence of Rgs2 and 5 (Rgs2/5 dbKO) affects cardiac function. We found that Rgs2/5 dbKO mice showed cardiac hypertrophy and a dilated left ventricle at baseline. Cardiac contractile response to a dobutamine stress test was sex-dependently reduced in male Rgs2/5 dbKO relative to WT mice. In addition, chronic systemic infusion of the [beta]-adrenergic receptor agonist, isoproterenol, led to marked exacerbation of cardiac hypertrophy in Rgs2/5 dbKO mice. When subjected to surgery-induced stress, male Rgs2/5 dbKO mice showed 80% mortality within 72 - 96 hours after surgery, accompanied by extreme hypertension and decreased cardiac contractile function. At the cellular level, cardiomyocytes from Rgs2/5 dbKO mice showed reduced contractile response to electrical pacing and exhibited irregular excitation-contraction coupling and death in response to increasing concentrations of different [beta]-adrenergic agonists. We conclude that RGS2 and 5 act synergistically within the heart to regulate signaling mechanisms that mediate cardiac structure and function. Thus, a thorough understanding of the G protein signaling regulation by multiple RGS proteins is key to identifying novel therapeutic targets for heart disease.