Regulator of G protein Signaling 2 and 5 Coordinate Their Activity to Control Cardiac Contractility

Abstract

Fine‐tuning of signaling via heterotrimeric G proteins by regulators of G protein signaling (RGS) proteins is critical to maintaining physiological homeostasis. Abnormal G protein signaling due to the loss of G protein regulation by RGS proteins is implicated in several diseases including cardiovascular disorders such as hypertension, cardiac hypertrophy, and heart failure. RGS proteins act as GTPase activating proteins (GAPs) to control the kinetics and amplitude of G protein signaling. Multiple RGS proteins are prominently expressed in the cardiovascular system; however, whether their activities/functions are coordinated to control G protein signaling and cardiovascular function is unknown. Here, we generated mice concurrently lacking RGS2 and 5 (Rgs2/5 dbKO) to determine how the dual absence of potent GAPs for Gq/11 and Gi/oclass G proteins affects cardiovascular function. Blood pressure and heart rate were monitored in conscious, freely moving mice via radiotelemetry. Surgical implantation of the radiotelemetry device induced marked systolic blood pressure increase in Rgs2/5 dbKO mice (WT: 140 ± 6 vs. dbKO: 170 ± 2 mmHg; p<0.01) at baseline, which gradually declined but remained elevated in Rgs2/5 dbKO relative to wild type (WT) mice, several days later. Whereas all WT mice survived the surgery, ~70–80% of male Rgs2/5 dbKO mice surprisingly died 72–96 hr post‐surgery. When subjected to cardiac stress test using acute dobutamine infusion and echocardiography or the invasive pressure‐volume loop analysis of cardiac function, male Rgs2/5 dbKO mice showed hypocontractile response and decreased ejection fraction relative to WT mice. Freshly isolated ventricular cardiomyocytes from male Rgs2/5 dbKO mice showed decreased fractional shortening (WT: 16.1 ± 4.3 vs. dbKO: 7.4 ± 1.1 %; p<0.01) but high calcium transients (WT: 117 ± 20 vs. dbKO: 198 ± 50 au; p=0.07) at baseline, and application of electrical field stimulation or low concentration of the non‐selective β‐adrenergic receptor agonist, isoproterenol (ISO), triggered premature calcium transients, tachyarrhythmia and death of cells from Rgs2/5 dbKO mice. Interestingly, cells from mice harboring just one copy of Rgs2 (Rgs2+/−, Rgs5−/−) but not Rgs5 (Rgs2−/−, Rgs5+/−) were resistant to low‐dose ISO‐induced arrhythmia. These results together suggest that RGS2 and 5 coordinate their activity to control cardiomyocyte excitation‐contraction coupling and normal cardiac rhythm.Support or Funding InformationNIH – NHLBI (1R01 HL139754‐01) and AHA Scientist Development Grant (16SDG27260276)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.