Gαi-coupled receptors play important roles in protecting the heart from ischemic injury. Regulator of G protein signaling (RGS) proteins suppress Gαi signaling by accelerating the GTPase activity of Gαi subunits. However, the roles of individual RGS proteins in modulating ischemic injury are unknown. In the present study, we investigated the impact of RGS6 deletion on myocardial sensitivity to ischemic injury. Hearts from RGS6 knockout (RGS6-/-) and wildtype (RGS6+/+) mice were subjected to 30 min ischemia and 2 hr reperfusion on a Langendorff heart apparatus. Infarcts in RGS6-/- hearts were significantly larger than infarcts in RGS6+/+ hearts. RGS6-/- hearts also exhibited increased phosphorylation of β-adrenergic receptors, ERK, and GRK2. Mitochondrial GRK2 as well as caspase-3 cleavage were increased significantly in RGS6-/- hearts compared to RGS6+/+ hearts following ischemia. Chronic propranolol treatment of mice prevented the observed increases in ischemic injury and phosphorylation of ERK and GRK2 observed in RGS6-/- hearts. Our findings suggest that loss of RGS6 predisposes the ventricle to pro-death signaling through the β2AR-ERK-GRK2 signaling axis and provide evidence for a protective role of RGS6 in the ischemic heart. Individuals expressing genetic polymorphisms that suppress the activity of RGS6 may be at increased risk of cardiac ischemic injury. Furthermore, the development of agents that increase RGS6 expression or activity might provide a novel strategy for the treatment of ischemic heart disease.
- The American Society for Pharmacology and Experimental Therapeutics