FAILURE TO OVEREXPRESS UROCORTIN FOLLOWING CARDIOPLEGIC ARREST MAKES THE HEART OF DIABETIC PATIENTS UNDERGOING ON-PUMP CORONARY ARTERY BYPASS GRAFTING MORE SUSCEPTIBLE TO APOPTOSIS AND CARDIAC DYSFUNCTION
Tiziano M. Scarabelli, M.D., St John Hospital & Medical Center/Wayne State University SOM, Detroit, MI, USA
Background. Molecular mechanisms responsible for the reported worse outcome of diabetic patients (DMP) after on-pump cardiac surgery (OPCS) remain unknown. Opposite effects have been reported for Urocortin (Ucn)/PKCe and PKCd, the former being cardio-protective and the latter pro-apoptotic.
Aim. We investigated the role of PKCe and PKCd in Ucn-induced cardio-protection in DMP and non-diabetic patients (NDMP) after OPCS.
Methods and Results. Two sequential biopsies were obtained from the right atrium of 27 DMP and 22 NDMP before Cardio-Pulmonary bypass (CPB) and 10 minutes after declamping. In post-cardioplegic NDMP, Ucn was induced at both mRNA and protein levels (p<0.01); conversely, post-cardioplegic induction was not observed in DMP (p=NS) and pre-cardioplegic levels of Ucn were 50% lower than NDMP (p<0.05). In NDMP, cardioplegic arrest increased PKC-e mRNA and protein (p<0.05), while overexpression of PKC-d was not seen. In contrast, DMP showed increased expression of PKCd (p<0.01) with no change in PKCe. Phosphorylation and mitochondrial relocation of PKCe were only detected in post-cardioplegic samples from NDMP, while nuclear and mitochondrial translocation of activated PKCd was mainly evident in post-cardioplegic samples from DMP. Apoptosis was over 2-fold higher in post-cardioplegic samples from DMP than NDMP. Apoptotic myocytes were Ucn-negative and exhibited nuclear and mitochondrial relocation of PKCd, while enhanced PKCe/mitochondrial colocalization was observed in viable, Ucn-positive, myocytes. The leakage of troponin I documented in DMP was higher than in NDP, although not statistically significant. Furthermore, despite a similar incidence of perioperative AMI, DMP did not show postoperative improvement of either systolic or diastolic function, which instead was seen in NDMP.
Conclusion. We report that in DMP, cardioplegic arrest failed to induce myocyte over-expression of Ucn and PKCe, but was associated with induction and mitochondrial relocation of PKCd, resulting in apoptosis. Failure to over-express Ucn makes the DMP more susceptible to apoptosis and cardiac dysfunction, thus contributing to the reported worse postsurgical outcomes.