Abstract P184: Coordinated Control of Cardiac Contractility By Multiple RGS Proteins

Abstract

Signaling via heterotrimeric G proteins is critical to maintaining cardiovascular homeostasis. Abnormal G protein signaling due to the loss of G protein regulation by proteins such as regulators of G protein signaling (RGS) proteins is implicated in several cardiovascular disorders such as hypertension, cardiac hypertrophy, and heart failure. RGS 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, it is unknown whether their activities/functions are coordinated to control G protein signaling and cardiovascular function. This study used mice concurrently lacking RGS2 and 5 ( Rgs2/5 dbKO) to determine how the dual loss of potent GAPs for Gq/11 and Gi/o class G proteins affects cardiovascular function. Blood pressure and heart rate in conscious, freely moving mice were monitored 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 above wild type (WT) control level several days later. Whereas all WT mice survived the surgery, ~70-80% of male Rgs2/5 dbKO mice died 72-96 hr post-surgery. When subjected to cardiac stress test using acute dobutamine infusion and echocardiography, male Rgs2/5 dbko mice showed hypocontractile response 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 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.