Myocardial immediate early gene activation after cardiopulmonary bypass with cardiac ischemia-reperfusion.

Abstract

The inflammatory process after cardiopulmonary bypass is accompanied by alterations in gene expression for various inflammatory mediators. To analyze differential gene expression after myocardial ischemia-reperfusion, subtraction hybridization was used to discover induction of TIS7/PC4, an immediate early gene heretofore not observed in the heart. This prompted characterization of the related immediate early genes c-fos and c-jun, by Northern analysis and in situ hybridization in human and lamb myocardium subjected to cardiopulmonary bypass with myocardial ischemia. For comparison, we analyzed expression of inducible nitric oxide synthase (iNOS), which requires cytokine-activation, resulting in a "delayed" response. In ischemic-reperfused myocardium at endcardiopulmonary bypass, c-fos, c-jun, and TIS7/PC4 were induced, whereas iNOS transcripts were undetectable. Expression patterns of c-fos and c-jun by in situ hybridization were markedly different; myocardial c-fos expression was diffuse and homogeneous, whereas c-jun expression was patchy with areas of intense focal localization. Cardiopulmonary bypass with myocardial ischemia rapidly induces the immediate early genes TIS7/PC4 (discovered by subtraction hybridization), and c-fos and c-jun (precursors to the transcriptional regulator AP-1). Immediate early genes presumably contribute to activation of inflammatory mediators after cardiopulmonary bypass and differences in their tissue expression patterns, as observed for c-fos and c-jun, presumably modulate their effect upon downstream gene activation.