title: Convergence of G protein-coupled receptor and S-nitrosylation signaling determines the outcome to cardiac ischemic injury.
abstract: 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.
authors.affiliation: 1Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Z Maggie
authors.initials: ZM
authors.lastname: Huang
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.forename: Fabio Vasconcelos
authors.initials: FV
authors.lastname: Fonseca
authors.forename: Hiroki
authors.initials: H
authors.lastname: Hayashi
authors.forename: Xiying
authors.initials: X
authors.lastname: Shang
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Hoffman
authors.forename: J Kurt
authors.initials: JK
authors.lastname: Chuprun
authors.forename: Xufan
authors.initials: X
authors.lastname: Tian
authors.forename: Doug G
authors.initials: DG
authors.lastname: Tilley
authors.forename: Muniswamy
authors.initials: M
authors.lastname: Madesh
authors.forename: David J
authors.initials: DJ
authors.lastname: Lefer
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Stamler
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000378:metabolism; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D026422:S-Nitrosoglutathione / Q000494:pharmacology; D026403:S-Nitrosothiols / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
chemical_list: D000318:Adrenergic beta-Agonists; D020030:Nitric Oxide Donors; D011943:Receptors, Adrenergic, beta; D018342:Receptors, Adrenergic, beta-1; D043562:Receptors, G-Protein-Coupled; D026403:S-Nitrosothiols; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D052250:Nitric Oxide Synthase Type III; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2; D007545:Isoproterenol