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Posts Tagged ‘Temple University School of Medicine’


G Protein–Coupled Receptor and S-Nitrosylation in Cardiac Ischemia

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

 

This recently published article delineates a role of G-protein-coupled receptor with S-nitrosylation in outcomes for acute coronary syndrome.

Convergence of G Protein–Coupled Receptor and S-Nitrosylation Signaling Determines the Outcome to Cardiac Ischemic Injury

Z. Maggie Huang1, Erhe Gao1, Fabio Vasconcelos Fonseca2,3, Hiroki Hayashi2,3, Xiying Shang1, Nicholas E. Hoffman1, J. Kurt Chuprun1, Xufan Tian4, Doug G. Tilley1, Muniswamy Madesh1, David J. Lefer5, Jonathan S. Stamler2,3,6, and Walter J. Koch1*
1 Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA
2 Institute for Transformative Molecular Medicine, Case Western Reserve Univ SOM, Cleveland, OH
3 Department of Medicine, Case Western Reserve University, Cleveland, OH
4 Department of Biochemistry, Thomas Jefferson University, Philadelphia, PA
5 Department  Surgery, Div of Cardiothoracic Surgery, Emory University School of Medicine, Atlanta, GA
6 University Hospitals Harrington Discovery Institute, Cleveland, OH

Sci. Signal., 29 Oct 2013; 6(299), p. ra95         http:dx.doi.org/10.1126/scisignal.2004225

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 are interdependent and converge 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.

* Corresponding author. E-mail: walter.koch@temple.edu
Citation: Z. M. Huang, E. Gao, F. V. Fonseca, H. Hayashi, X. Shang, N. E. Hoffman, J. K. Chuprun, X. Tian, D. G. Tilley, M. Madesh, D. J. Lefer, J. S. Stamler, W. J. Koch, Convergence of G Protein–Coupled Receptor and S-Nitrosylation Signaling Determines the Outcome t

 Editor’s Summary

Sci. Signal., 29 Oct 2013; 6(299), p. ra95 [DOI: 10.1126/scisignal.2004225]

NO More Heart Damage

Damage caused by the lack of oxygen and nutrients that occurs during myocardial ischemia can result in heart failure. A therapeutic strategy that helps to limit the effects of heart failure is to

  • increase signaling through G protein–coupled receptors (GPCRs)
  • by inhibiting GRK2 (GPCR kinase 2), a kinase that
    • desensitizes GPCRs.

Another therapeutic strategy provides S-nitrosothiols, such as nitric oxide, which can be

  • added to proteins in a posttranslational modification called S-nitrosylation.

Huang et al. found that the ability of S-nitrosothiols to enhance cardiomyocyte survival after ischemic injury required the S-nitrosylation of GRK2, a modification that inhibits this kinase. Mice bearing a form of GRK2 that could not be S-nitrosylated 

  • were more susceptible to cardiac damage after ischemia.

These results suggest that therapeutic strategies that promote the S-nitrosylation of GRK2 could be used to treat heart failure after myocardial ischemia.

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