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Cardioprotective Role of Regulator of G Protein Signaling 6 in the Ischemic Heart
Author(s) -
Rorabaugh Boyd R.,
Chakravarti Bandana,
Seeley Sarah L.,
Bui Albert D.,
Yang Jianqi,
Watts Stephanie W,
Neubig Richard R.,
Fisher Rory A
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.846.8
Subject(s) - regulator of g protein signaling , mapk/erk pathway , ventricle , knockout mouse , medicine , biology , phosphorylation , microbiology and biotechnology , receptor , g protein , gtpase activating protein
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 2 ‐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 β 2 AR‐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. Support or Funding Information This work was supported by the National Institute of General Medicine [GM39561 to RRN], National Cancer institute [CA161882 to RAF], the American Heart Association [14GRNT20460208 to RAF], and an Ohio Northern University Bower and Bennet Endowment Award to BRR