title: Regulator of G Protein Signaling 6 Protects the Heart from Ischemic Injury.
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.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, Raabe College of Pharmacy, Ohio Northern University, Ada, Ohio (B.R.R., N.W.M., S.L.S., A.D.B.); Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, Iowa (B.C., J.Y., R.A.F.); and Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan (S.W.W., R.R.N.) b-rorabaugh@onu.edu.
authors.forename: Boyd R
authors.initials: BR
authors.lastname: Rorabaugh
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, Raabe College of Pharmacy, Ohio Northern University, Ada, Ohio (B.R.R., N.W.M., S.L.S., A.D.B.); Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, Iowa (B.C., J.Y., R.A.F.); and Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan (S.W.W., R.R.N.).
authors.forename: Bandana
authors.initials: B
authors.lastname: Chakravarti
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, Raabe College of Pharmacy, Ohio Northern University, Ada, Ohio (B.R.R., N.W.M., S.L.S., A.D.B.); Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, Iowa (B.C., J.Y., R.A.F.); and Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan (S.W.W., R.R.N.).
authors.forename: Nathaniel W
authors.initials: NW
authors.lastname: Mabe
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, Raabe College of Pharmacy, Ohio Northern University, Ada, Ohio (B.R.R., N.W.M., S.L.S., A.D.B.); Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, Iowa (B.C., J.Y., R.A.F.); and Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan (S.W.W., R.R.N.).
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Seeley
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, Raabe College of Pharmacy, Ohio Northern University, Ada, Ohio (B.R.R., N.W.M., S.L.S., A.D.B.); Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, Iowa (B.C., J.Y., R.A.F.); and Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan (S.W.W., R.R.N.).
authors.forename: Albert D
authors.initials: AD
authors.lastname: Bui
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, Raabe College of Pharmacy, Ohio Northern University, Ada, Ohio (B.R.R., N.W.M., S.L.S., A.D.B.); Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, Iowa (B.C., J.Y., R.A.F.); and Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan (S.W.W., R.R.N.).
authors.forename: Jianqi
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, Raabe College of Pharmacy, Ohio Northern University, Ada, Ohio (B.R.R., N.W.M., S.L.S., A.D.B.); Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, Iowa (B.C., J.Y., R.A.F.); and Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan (S.W.W., R.R.N.).
authors.forename: Stephanie W
authors.initials: SW
authors.lastname: Watts
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, Raabe College of Pharmacy, Ohio Northern University, Ada, Ohio (B.R.R., N.W.M., S.L.S., A.D.B.); Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, Iowa (B.C., J.Y., R.A.F.); and Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan (S.W.W., R.R.N.).
authors.forename: Richard R
authors.initials: RR
authors.lastname: Neubig
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, Raabe College of Pharmacy, Ohio Northern University, Ada, Ohio (B.R.R., N.W.M., S.L.S., A.D.B.); Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, Iowa (B.C., J.Y., R.A.F.); and Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan (S.W.W., R.R.N.).
authors.forename: Rory A
authors.initials: RA
authors.lastname: Fisher
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism*; D015195:Drug Design; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism*; D009203:Myocardial Infarction / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D017202:Myocardial Ischemia / Q000150:complications / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D020011:Protective Agents / Q000378:metabolism; D020710:RGS Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D020011:Protective Agents; D020710:RGS Proteins; C485692:Rgs6 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2; D053148:Caspase 3