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Cardioplegia prevents ischemia-induced transcriptional alterations of cytoprotective genes in rat hearts: a DNA microarray study.

Schomisch SJ, Murdock DG, Hedayati N, Carino JL, Lesnefsky EJ, Cmolik BL

Division of Cardiothoracic Surgery, Case Western Reserve University, University Hospitals of Cleveland, Cleveland, Ohio 44106-5011, USA.

BACKGROUND: Energy conservation and calcium homeostasis contribute to myocardial protection provided by hyperkalemic cardioplegia during ischemia. Complimenting these established mechanisms of protection, previous work suggested that activation of cytoprotective signaling pathways also contributes to reduced injury with cardioplegia. We proposed that cardioplegia would recruit cytoprotective pathways and investigated the transcriptional response of the heart after cardioplegia-protected ischemia compared with that after ischemia alone. METHODS: Isolated perfused rat hearts underwent 40 minutes of global ischemia alone or with St Thomas cardioplegia, followed by 120 minutes of reperfusion. The expression profiles of isolated RNA were determined by using Affymetrix microarrays and assessed by comparing cardioplegia-protected hearts and hearts undergoing unprotected ischemia with time-matched control hearts. The content of selected proteins was assessed by means of immunoblotting. RESULTS: Cardioplegia preserved the expression of multiple genes involved in carbohydrate and fatty acid metabolism, glycolysis, and electron transport compared with ischemia alone. The expression of the sodium-calcium exchanger and ryanodine receptor was preserved in line with the ability of cardioplegia to decrease calcium overload. The expression of multiple cytoprotective molecules, including protein-tyrosine kinase, calcineurin B, p38 mitogen-activated protein kinase, voltage-dependent anion channel, protein kinase C , heat shock protein 70, and manganese superoxide dismutase all showed decreased expression in ischemia but were preserved to near nonischemic levels by cardioplegia. CONCLUSION: Cardioplegia during ischemia maintained an expression profile similar to that seen in nonischemic hearts for genes involved in energy conservation, calcium homeostasis, and cytoprotective pathways, whereas ischemia alone did not. Exposing the transcriptional differences in cytoprotective genes during untreated and cardioplegia-treated ischemia provides valuable insight into an additional mechanism of cardioprotection induced by cardioplegia.

Published 10 October 2005 in J Thorac Cardiovasc Surg, 130(4): 1151.
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