Convergence of G protein-coupled receptor and S-nitrosylation signaling determines the outcome to cardiac ischemic injury.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Huang, ZM; Gao, E; Fonseca, FV; Hayashi, H; Shang, X; Hoffman, NE; Chuprun, JK; Tian, X; Tilley, DG; Madesh, M; Lefer, DJ; Stamler, JS; Koch, WJ

Published Date

  • October 29, 2013

Published In

Volume / Issue

  • 6 / 299

Start / End Page

  • ra95 -

PubMed ID

  • 24170934

Pubmed Central ID

  • 24170934

Electronic International Standard Serial Number (EISSN)

  • 1937-9145

International Standard Serial Number (ISSN)

  • 1945-0877

Digital Object Identifier (DOI)

  • 10.1126/scisignal.2004225

Language

  • eng