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

Z. Maggie Huang, Erhe Gao, Fabio Vasconcelos Fonseca, Hiroki Hayashi, Xiying Shang, Nicholas E. Hoffman, J. Kurt Chuprun, Xufan Tian, Doug G. Tilley, Madesh Muniswamy, David J. Lefer, Jonathan S. Stamler, Walter J. Koch

Research output: Contribution to journalArticle

39 Citations (Scopus)

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 distinctmolecular 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.

Original languageEnglish (US)
JournalScience Signaling
Volume6
Issue number299
DOIs
StatePublished - Oct 29 2013
Externally publishedYes

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G-Protein-Coupled Receptors
Phosphotransferases
Wounds and Injuries
Nitric Oxide Synthase Type III
Muscle Cells
Myocardial Ischemia
Nitric Oxide
Heart Failure
G-Protein-Coupled Receptor Kinase 2
Chemical activation
Bioactivity
Cause of Death
Myocardium
Enzymes
Pharmaceutical Preparations
Therapeutics

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Convergence of G protein-coupled receptor and S-nitrosylation signaling determines the outcome to cardiac ischemic injury. / Maggie Huang, Z.; Gao, Erhe; Fonseca, Fabio Vasconcelos; Hayashi, Hiroki; Shang, Xiying; Hoffman, Nicholas E.; Kurt Chuprun, J.; Tian, Xufan; Tilley, Doug G.; Muniswamy, Madesh; Lefer, David J.; Stamler, Jonathan S.; Koch, Walter J.

In: Science Signaling, Vol. 6, No. 299, 29.10.2013.

Research output: Contribution to journalArticle

Maggie Huang, Z, Gao, E, Fonseca, FV, Hayashi, H, Shang, X, Hoffman, NE, Kurt Chuprun, J, Tian, X, Tilley, DG, Muniswamy, M, Lefer, DJ, Stamler, JS & Koch, WJ 2013, 'Convergence of G protein-coupled receptor and S-nitrosylation signaling determines the outcome to cardiac ischemic injury', Science Signaling, vol. 6, no. 299. https://doi.org/10.1126/scisignal.2004225
Maggie Huang, Z. ; Gao, Erhe ; Fonseca, Fabio Vasconcelos ; Hayashi, Hiroki ; Shang, Xiying ; Hoffman, Nicholas E. ; Kurt Chuprun, J. ; Tian, Xufan ; Tilley, Doug G. ; Muniswamy, Madesh ; Lefer, David J. ; Stamler, Jonathan S. ; Koch, Walter J. / Convergence of G protein-coupled receptor and S-nitrosylation signaling determines the outcome to cardiac ischemic injury. In: Science Signaling. 2013 ; Vol. 6, No. 299.
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