Journal article
Regulator of G Protein Signaling 6 Protects the Heart from Ischemic Injury
The Journal of pharmacology and experimental therapeutics, Vol.360(3), pp.409-416
03/2017
DOI: 10.1124/jpet.116.238345
PMCID: PMC5325075
PMID: 28035008
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 β
-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 β
AR-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.
Details
- Title: Subtitle
- Regulator of G Protein Signaling 6 Protects the Heart from Ischemic Injury
- Creators
- Boyd R Rorabaugh - 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.eduBandana Chakravarti - 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.)Nathaniel W Mabe - 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.)Sarah L Seeley - 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.)Albert D Bui - 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.)Jianqi Yang - 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.)Stephanie W Watts - 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.)Richard R Neubig - 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.)Rory A Fisher - 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.)
- Resource Type
- Journal article
- Publication Details
- The Journal of pharmacology and experimental therapeutics, Vol.360(3), pp.409-416
- Publisher
- United States
- DOI
- 10.1124/jpet.116.238345
- PMID
- 28035008
- PMCID
- PMC5325075
- ISSN
- 0022-3565
- eISSN
- 1521-0103
- Grant note
- R01 CA161882 / NCI NIH HHS R01 GM039561 / NIGMS NIH HHS
- Language
- English
- Date published
- 03/2017
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984040348202771
Metrics
17 Record Views