RT Journal Article
SR Electronic
T1 Convergence of G Protein–Coupled Receptor and S-Nitrosylation Signaling Determines the Outcome to Cardiac Ischemic Injury
JF Science Signaling
JO Sci. Signal.
FD American Association for the Advancement of Science
SP ra95
OP ra95
DO 10.1126/scisignal.2004225
VO 6
IS 299
A1 Huang, Z. Maggie
A1 Gao, Erhe
A1 Fonseca, Fabio Vasconcelos
A1 Hayashi, Hiroki
A1 Shang, Xiying
A1 Hoffman, Nicholas E.
A1 Chuprun, J. Kurt
A1 Tian, Xufan
A1 Tilley, Doug G.
A1 Madesh, Muniswamy
A1 Lefer, David J.
A1 Stamler, Jonathan S.
A1 Koch, Walter J.
YR 2013
UL http://stke.sciencemag.org/content/6/299/ra95.abstract
AB Heart failure caused by ischemic heart disease is a leading cause of death in the developed world. Treatment is currently centered on regimens involving G protein–coupled receptors (GPCRs) or nitric oxide (NO). These regimens are thought to target distinct molecular pathways. We showed that these pathways were interdependent and converged on the effector GRK2 (GPCR kinase 2) to regulate myocyte survival and function. Ischemic injury coupled to GPCR activation, including GPCR desensitization and myocyte loss, required GRK2 activation, and we found that cardioprotection mediated by inhibition of GRK2 depended on endothelial nitric oxide synthase (eNOS) and was associated with S-nitrosylation of GRK2. Conversely, the cardioprotective effects of NO bioactivity were absent in a knock-in mouse with a form of GRK2 that cannot be S-nitrosylated. Because GRK2 and eNOS inhibit each other, the balance of the activities of these enzymes in the myocardium determined the outcome to ischemic injury. Our findings suggest new insights into the mechanism of action of classic drugs used to treat heart failure and new therapeutic approaches to ischemic heart disease.