Published online before print August 31, 2006, doi: 10.1161/01.RES.0000243995.74395.f8
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Submitted on February 24, 2006
Revised on August 11, 2006
Accepted on August 22, 2006
Proteomic Analysis of Pharmacological Preconditioning. Novel Protein Targets Converge to Mitochondrial Metabolism Pathways
D. Kent Arrell ;
From the Department of Physiology (D.K.A., S.T.E., J.E.V.E.), Queen’s University, Kingston, Ontario, Canada; and Departments of Medicine (S.T.E., Y.G., M.M., E.M., J.E.V.E.), Biological Chemistry (L.A.K., Y.H.K., P.L.P., J.E.V.E.), Pediatrics (J.R., A.M.M.), and Biomedical Engineering (J.E.V.E.), The Johns Hopkins University, Baltimore, Md. Present address for D.K.A.: Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minn.
* To whom correspondence should be addressed. E-mail: jvaneyk1{at}jhmi.edu.
Ischemic preconditioning is characterized by resistance to ischemia reperfusion injury in response to previous short ischemic episodes, a protective effect that can be mimicked pharmacologically. The underlying mechanism of protection remains controversial and requires greater understanding before it can be fully exploited therapeutically. To investigate the overall effect of preconditioning on the myocardial proteome, isolated rabbit ventricular myocytes were treated with drugs known to induce preconditioning, adenosine or diazoxide (each at 100 µmol/L for 60 minutes). Their protein profiles were then compared with vehicle-treated controls (n=4 animals per treatment) using a multitiered 2D gel electrophoresis approach. Of 28 significantly altered protein spots, 19 nonredundant proteins were identified (5 spots remained unidentified). The majority of these proteins are involved in mitochondrial energetics, including subunits of tricarboxylic acid cycle enzymes and oxidative phosphorylation complexes. These changes were not indiscriminate, with only a small number of enzymes or complex subunits altered, indicating a very specific and targeted affect of these 2 preconditioning mimetics. Among the changes were shifts in the extent of posttranslational modification for 4 proteins. One of these, the adenosine-induced phosphorylation of the ATP synthase 
subunit, was fully characterized with the identification of 5 novel phosphorylation sites. This proteomics approach provides an overall assessment of the cellular response to pharmacological treatment with adenosine and diazoxide and identifies a distinct subset of enzymes and protein complex subunit that may underlie the preconditioned phenotype.
Key words: ATP synthase • phosphorylation • preconditioning • proteomics
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