G protein-coupled receptor kinase 2 activity impairs cardiac glucose uptake and promotes insulin resistance after myocardial ischemia.

Authors:
Michele Ciccarelli
Michele Ciccarelli
University of Salerno
Fisciano | Italy
Dr. Giuseppe Rengo, MD, PhD
Dr. Giuseppe Rengo, MD, PhD
Department of Translational Medical Sciences - University of Naples Federico II
Associate Professor
Cardiology
Naples, Italy | Italy
Dr. Erhe Gao, MD, PhD
Dr. Erhe Gao, MD, PhD
Temple University School of Medicine
Professor
Philadelphia, PA | United States
Zhengyu Wei
Zhengyu Wei
University of Pennsylvania School of Medicine
Philadelphia | United States
Raymond J Peroutka
Raymond J Peroutka
Department of Medicine
Madison | United States
Jessica I Gold
Jessica I Gold
Center for Translational Medicine
Arlington | United States
Anna Gumpert
Anna Gumpert
Center for Translational Medicine
Arlington | United States

Circulation 2011 May 25;123(18):1953-62. Epub 2011 Apr 25.

George Zallie and Family Laboratory for Cardiovascular Gene Therapy, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, USA.

Background: Alterations in cardiac energy metabolism downstream of neurohormonal stimulation play a crucial role in the pathogenesis of heart failure. The chronic adrenergic stimulation that accompanies heart failure is a signaling abnormality that leads to the upregulation of G protein-coupled receptor kinase 2 (GRK2), which is pathological in the myocyte during disease progression in part owing to uncoupling of the β-adrenergic receptor system. In this study, we explored the possibility that enhanced GRK2 expression and activity, as seen during heart failure, can negatively affect cardiac metabolism as part of its pathogenic profile.

Methods And Results: Positron emission tomography studies revealed in transgenic mice that cardiac-specific overexpression of GRK2 negatively affected cardiac metabolism by inhibiting glucose uptake and desensitization of insulin signaling, which increases after ischemic injury and precedes heart failure development. Mechanistically, GRK2 interacts with and directly phosphorylates insulin receptor substrate-1 in cardiomyocytes, causing insulin-dependent negative signaling feedback, including inhibition of membrane translocation of the glucose transporter GLUT4. This identifies insulin receptor substrate-1 as a novel nonreceptor target for GRK2 and represents a new pathological mechanism for this kinase in the failing heart. Importantly, inhibition of GRK2 activity prevents postischemic defects in myocardial insulin signaling and improves cardiac metabolism via normalized glucose uptake, which appears to participate in GRK2-targeted prevention of heart failure.

Conclusions: Our data provide novel insights into how GRK2 is pathological in the injured heart. Moreover, it appears to be a critical mechanistic link within neurohormonal crosstalk governing cardiac contractile signaling/function through β-adrenergic receptors and metabolism through the insulin receptor.

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Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.110.988642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3113597PMC
May 2011
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45 Citations
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References

(Supplied by CrossRef)
An evaluation of myocardial fatty acid and glucose uptake using PET with [18F]fluoro-6-thia-heptadecanoic acid and [18F]FDG in patients with congestive heart failure
Taylor M et al.
J Nucl Med 2001

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