J. Feng1, A. K. Singh1, J. Liang1, Y. Liu1, F. W. Sellke1 1Brown University School Of Medicine,Cardiothoracic/Surgery,Providence, RI, USA
Introduction: Cardiac surgery with cardiopulmonary bypass (CPB) is often associated with the increased vascular permeability/tissue edema, microvascular endothelial cell injury/dysfunction. Especially, these disturbances are more pronounced in patients with poorly controlled diabetes. Recent study has demonstrated that the increased permeability after cardiopleogic arrest/CPB is associated with changes in the expression/phosphorylation of adherence-junction-proteins in the coronary vasculature in patients with type-2 diabetes (T2DM). We hypothesized that T2DM may be associated with altered adherence-junction-protein expression/phosphorylation of skeletal muscle/vessel in the setting of CPB . The aim of the current study was to investigate the changes in adherens-junction-proteins, such as VE-cadherin, and β-catenin of skeletal muscle and vessels in patients with or without T2DM in the setting of CPB and coronary artery bypass graft (CABG) surgery.
Methods: Chest wall skeletal muscle tissue was harvested pre- and post-CPB from the controlled diabetic (HbA1c: 6.3 ± 0.1), uncontrolled diabetic (HbA1c: 9.6 ± 0.3) and non-diabetic patients (HbA1c: 5.4 ± 0.1) undergoing CABG surgery (n = 6/group). The expression/phosphorylation of adherence-junction-proteins such as, VE-cadherin and β-catenin were assessed by immunoblotting and immuno-histochemistry. Skeletal-muscle-arteriolar endothelial function was assessed by videomicroscopy in response to the endothelium-dependent vasodilator substance P.
Results:There were no significant differences in basal protein expression of VE-cadherin between UDM and CDM or ND patients or between pre- and post-CPB among groups. The level of pre-CPB phosphorylated VE-cadherin tends to be 25% higher in the UDM group compared with ND (P = 0.03). CPB induced more phosphorylation of VE-cadherin (21% in ND; 30% in CDM and 43% vs. pre-CPB; P<0.05, respectively) and this effect was more pronounced in the UDM group (P<0.05 vs. ND or CDM). The post-CPB β-catenin was significantly decreased as compared with pre-CPB in all three groups (P<0.05) and the decrease was more pronounced in the UDM group (P<0.05). There were significantly decreases in vasodilatory response of skeletal muscle arterioles to substance P after CPB in all three groups (P<0.05). This alteration was more pronounced in the UDM patients (P<0.05).
Conclusion: These findings suggest that poorly controlled diabetes down-regulates endothelial adherence-junction-protein expression of skeletal muscle/vessel tissues in the setting of CPB. The enhanced tyrosine phosphorylation of VE-cadherin and degradation of β-catenin indicates deterioration of these proteins and the damage of the cell-cell endothelial junctions, specifically in the diabetic vessels. These alterations may lead to the increases in periphral vascular permeability and endothelial dysfunction and affect the outcomes in diabetic patients after CPB/cardiac surgery.