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Posts Tagged ‘Case Western Reserve University’


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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Malaria Genomes

 

Curator: Larry H Bernstein, MD, FCAP

 

 Five Malaria Genomes Sequenced

Zimmerman et al.
Whole Genome Sequencing of Field Isolates Provides Robust Characterization of Genetic Diversity in Plasmodium vivax.
Scientists have sequenced the entire genomes of five Plasmodium vivax strains taken from the blood of patients on different continents, providing
  • a wealth of new data to help in the future mapping of malarial parasite traits such as
  • drug resistance, and
determine how different strains are geographically distributed.
  • identified over 80,000 SNPs that can form the basis of association studies and
  • population surveys to study the diversity of P. vivax in a single region.
Malaria.

Malaria. (Photo credit: maestro garabito/escuela potosina)

Malaria distribution map. Most countries with ...

Malaria distribution map. Most countries with a high distribution of malaria also have a high distribution of parasitic worm infections. (Photo credit: Wikipedia)

English: This thin film Giemsa stained microgr...

English: This thin film Giemsa stained micrograph reveals a mature Plasmodium vivax trophozoite. P. vivax trophozoites show amoeboid cytoplasm, large chromatin dots, and fine, yellowish-brown pigment. RBCs are enlarged 1 1/2 – 2X, and may be distorted. If visible, Schüffner’s dots may appear finer than those seen in P. vivax. (Photo credit: Wikipedia)

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A recent study by researchers at Case Western Reserve University is likely to promise a new life to Alzheimer’s victims and their loved ones.

Alzheimer’s disease (AD) is associated with impaired clearance of β-amyloid (Aβ) from the brain, a process normally facilitated by apolipoprotein E (apoE). Oral administration of the retinoid X receptors (RXRs) agonist bexarotene to a mouse model of AD resulted in enhanced clearance of soluble within hours in an apoE-dependent manner. Aβ plaque area was reduced more than 50% within just 72 hours. Furthermore, bexarotene stimulated the rapid reversal of cognitive, social, and olfactory deficits and improved neural circuit function.

Thus, researchers hope and believe that, RXR activation stimulates physiological Aβ clearance mechanisms, resulting in the rapid reversal of a broad range of Aβ-induced deficits in humans as well.

Bexarotene has been approved for the treatment of cancer by the U.S. Food and Drug Administration for more than a decade. It has a good safety and side-effect profile, which researchers hope will help speed the transition to clinical trials of the drug.

source

Reported by: Dr. V. S. Karra, Ph.D

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