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CRYAB and HSPB2 deficiency alters cardiac metabolism and paradoxically confers protection against myocardial ischemia in aging mice. Am J Physiol Heart Circ Physiol 2007 Nov;293(5):H3201-9

Date

09/18/2007

Pubmed ID

17873008

Pubmed Central ID

PMC3683980

DOI

10.1152/ajpheart.01363.2006

Scopus ID

2-s2.0-36149001329   40 Citations

Abstract

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 ( approximately 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.

Author List

Benjamin IJ, Guo Y, Srinivasan S, Boudina S, Taylor RP, Rajasekaran NS, Gottlieb R, Wawrousek EF, Abel ED, Bolli R

Author

Ivor J. Benjamin MD Center Director, Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Aging
Animals
Female
HSP27 Heat-Shock Proteins
Heat-Shock Proteins
Male
Mice
Mice, Knockout
Myocardial Ischemia
Myocardium
alpha-Crystallin B Chain
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a