Abstract
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 this study, we investigated the effect of RGS6 deletion on myocardial sensitivity to ischemic injury. Hearts from RGS6 knockout (RGS6−/−) and RGS6 wild-type (RGS6+/+) mice were subjected to 30 minutes of ischemia and 2 hours of 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 β2-adrenergic receptors and G protein–coupled receptor kinase 2 (GRK2). Mitochondrial GRK2 as well as caspase-3 cleavage were increased significantly in RGS6−/− hearts compared with RGS6+/+ hearts after ischemia. Chronic propranolol treatment of mice prevented the observed increases in ischemic injury and the GRK2 phosphorylation observed in RGS6−/− hearts. Our findings suggest that loss of RGS6 predisposes the ventricle to prodeath signaling through a β2AR-GRK2–dependent signaling mechanism, and they 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.
Footnotes
- Received October 17, 2016.
- Accepted December 28, 2016.
This research was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant R01 GM39561 (to R.R.N.)], the National Institutes of Health National Cancer Institute [Grant R01 CA161882 (to R.A.F.)], the American Heart Association [Grant 14GRNT20460208 (to R.A.F.)], and the Ohio Northern University [Bower and Bennet Endowment Award (to B.R.R.)].
↵1 Current affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina.
↵2 Current affiliation: Ohio University College of Osteopathic Medicine, Athens, Ohio.
- Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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