Induction of early immediate genes and programmed cell death following cardioplegic arrest in human hearts

Objective: Under experimental conditions cardiac stress may induce early immediate genes. Of these, heat shock proteins like hsp 70 have been linked to preconditioning and cellular salvage. Protooncogenes like c-fos and c-jun act as transcription factors for other genes and may be involved in the regulation of programmed cell death. Methods: Patients, 30, undergoing elective coronary artery bypass grafting, received either cold antegrade St. Thomas II or Bretschneider or Hamburg cardioplegic solutions with ten patients in each group. Tissue from right atria was removed before cardiopulmonary bypass and following cardioplegic arrest and reperfusion. Tissues were examined by Northern blots, immunohistochemistry, and in situ nick-end labeling of fragmented DNA as evidence for programmed cell death. Results: There were no significant preoperative or operative differences between groups. Following cardioplegia and reperfusion, a significant induction of both protooncogene and heat shock protein 70 mRNA was observed. Whereas levels of hsp 70 were increased about two-fold in all groups (PB 0.05), induction of c-fos and c-jun was most pronounced following the Hamburg cardioplegic solution (PB 0.05 versus baseline and for differences to other groups). Induction on the protein level was confirmed using immunohistochemistry that furthermore, identified cardiac myocytes and endothelial cells being the cell types that expressed these genes. In contrast to prebypass samples, in situ nick-end labeling of fragmented DNA following cardioplegic arrest and reperfusion was positive, preponderately in subendocardial myocytes and endothelial cells. Conclusions: Cold cardioplegia is a potent stimulus for induction of the early immediate genes examined in human hearts. Increased expression of protooncogenes may be deleterious to cardiac myocytes as indicated by in situ nick-end labeling of DNA fragments. Differences in gene induction may add additional information for the evaluation of different cardioplegic strategies. © 1997 Elsevier Science B.V.