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This Article Full Text Full Text (PDF) All Versions of this Article: 293/5/H3201    most recent 01363.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Benjamin, I. J. Articles by Bolli, R. Search for Related Content PubMed PubMed Citation Articles by Benjamin, I. J. Articles by Bolli, R.

CRYAB and HSPB2 deficiency alters cardiac metabolism and paradoxically confers protection against myocardial ischemia in aging mice

¹Center for Cardiovascular Translational Biomedicine, University of Utah, School of Medicine, Salt Lake City, Utah; ²Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky; ³Program in Human Molecular Biology and Genetics, Division of Endocrinology and Metabolism, University of Utah, Salt Lake City, Utah; ⁴Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California; and ⁵National Eye Institute, National Institutes of Health, Bethesda, Maryland

Submitted 13 December 2006 ; accepted in final form 1 September 2007

The abundantly expressed small molecular weight proteins, CRYAB and HSPB2, have been implicated in cardioprotection ex vivo. However, the biological roles of CRYAB/HSPB2 coexpression for either ischemic preconditioning and/or protection in situ remain poorly defined. Wild-type (WT) and age-matched (5–9 mo) CRYAB/HSPB2 double knockout (DKO) mice were subjected either to 30 min of coronary occlusion and 24 h of reperfusion in situ or preconditioned with a 4-min coronary occlusion/4-min reperfusion x 6, before similar ischemic challenge (ischemic preconditioning). Additionally, WT and DKO mice were subjected to 30 min of global ischemia in isolated hearts ex vivo. All experimental groups were assessed for area at risk and infarct size. Mitochondrial respiration was analyzed in isolated permeabilized cardiac skinned fibers. As a result, DKO mice modestly altered heat shock protein expression. Surprisingly, infarct size in situ was reduced by 35% in hearts of DKO compared with WT mice (38.8 ± 17.9 vs. 59.8 ± 10.6% area at risk, P < 0.05). In DKO mice, ischemic preconditioning was additive to its infarct-sparing phenotype. Similarly, infarct size after ischemia and reperfusion ex vivo was decreased and the production of superoxide and creatine kinase release was decreased in DKO compared with WT mice (P < 0.05). In permeabilized fibers, ADP-stimulated respiration rates were modestly reduced and calcium-dependent ATP synthesis was abrogated in DKO compared with WT mice. In conclusion, contrary to expectation, our findings demonstrate that CRYAB and HSPB2 deficiency induces profound adaptations that are related to 1) a reduction in calcium-dependent metabolism/respiration, including ATP production, and 2) decreased superoxide production during reperfusion. We discuss the implications of these disparate results in the context of phenotypic responses reported for CRYAB/HSPB2-deficient mice to different ischemic challenges.

small molecular weight heat shock protein; cardioprotection; aging; preconditioning; reperfusion injury