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.