Differential cardiac gene expression during cardiopulmonary bypass: ischemia-independent upregulation of proinflammatory genes.
OBJECTIVE: Cardiac surgery with cardiopulmonary bypass induces both systemic and local inflammatory responses implicated in the pathogenesis of myocardial dysfunction. Multifactorial perioperative sources of myocardial injury complicate understanding of the molecular mechanisms involved. By using microarray technology, this study examines myocardial gene expression responses to cardiopulmonary bypass in the absence of cardioplegic arrest and ischemia-reperfusion injury. METHODS: We used a unique rat model of cardiopulmonary bypass in which sternotomy, direct operations on the heart, aortic crossclamping, and cardioplegic arrest were not performed. Hearts from 6 animals randomized to either 90 minutes of cardiopulmonary bypass or sham control animals were used to perform cDNA microarray analyses of 2343 genes. Real-time quantitative polymerase chain reaction was used to confirm the microarray results for a subset of genes. RESULTS: Compared with sham-operated control animals, myocardium from animals undergoing cardiopulmonary bypass revealed 42 differentially expressed genes. Upregulated genes include the transcription activator nuclear factor kappaB, adhesion molecules (vascular cell adhesion molecule 1 and P-selectin), and interleukin 6 receptor subunits; downregulated genes include transforming growth factor beta receptor 2, tissue inhibitor of metalloproteinase 3, and mitogen-activated protein kinase 1. Distinct proinflammatory gene cascades were confirmed by means of category overrepresentation analysis. CONCLUSIONS: This study represents an initial report on the use of microarray technology to elucidate cardiac transcriptional programs in response to cardiopulmonary bypass-specific injury in vivo. These preliminary findings, combined with future functional genomic studies superimposing ischemia and reperfusion and other inflammatory stimuli, should improve our understanding of the molecular regulatory networks involved in myocardial responses to injury and aid in the development of novel cardioprotective and perfusion strategies.
Podgoreanu, MV; Michelotti, GA; Sato, Y; Smith, MP; Lin, S; Morris, RW; Grocott, HP; Mathew, JP; Schwinn, DA
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