Effects of diabetes and cardiopulmonary bypass on expression of adherens junction proteins in human peripheral tissue

Abstract

Background: We investigated the changes in adherens junction proteins, such as vascular endothelial-cadherin and β-catenin, of skeletal muscle and vessels in patients with or without diabetes in the setting of cardiopulmonary bypass and cardiac operation.

Methods: Skeletal muscle tissue samples were harvested pre- and post-cardiopulmonary bypass from nondiabetic (hemoglobin A1c: 5.4 ± 0.1), controlled diabetic (hemoglobin A1c: 6.3 ± 0.1), and uncontrolled diabetic patients (hemoglobin A1c: 9.6 ± 0.3) undergoing coronary artery bypass grafting operation (n = 8 per group). The expression/phosphorylation of adherens junction proteins vascular endothelial-cadherin and β-catenin were assessed by immunoblotting and immuno-histochemistry. Endothelial function of skeletal muscle arterioles was determined by videomicroscopy in response to the vasodilator substance P.

Results: The protein expression of total vascular endothelial-cadherin was not changed at baseline or between pre-and post-cardiopulmonary bypass among groups. The pre-cardiopulmonary bypass level of phospho-vascular endothelial-cadherin was found to be significantly increased in the uncontrolled diabetic patients group compared with the nondiabetic or controlled diabetic groups (P < .05). The post-cardiopulmonary bypass levels of phospho-vascular endothelial-cadherin were significantly increased compared with pre-cardiopulmonary bypass in all groups (P < .05 each), and this increase was greater in the uncontrolled diabetic patients group than that of the nondiabetic or controlled diabetic groups (P < .05). Expression of basal β-catenin protein in the uncontrolled diabetic group was decreased compared with nondiabetic or controlled diabetic groups (P < .05). There were significant decreases in the β-catenin protein expression between pre- and post-cardiopulmonary bypass in all 3 groups (P < .05 each), and this decrease was greater in the uncontrolled diabetic patients group than the nondiabetic group (P < .05). There were decreases in the relaxation response of skeletal muscle arterioles to substance P after cardiopulmonary bypass in all 3 groups (P < .05), and this alteration was more pronounced in the uncontrolled diabetic patients (P < .05).

Conclusion: Uncontrolled diabetes causes inactivation and reduction in the expression of endothelial adherens junction proteins in the arterioles of skeletal muscle early after cardiopulmonary bypass. The enhanced phosphorylation of vascular endothelial-cadherin and degradation of β-catenin indicate deterioration of these proteins and damage of the cell-cell endothelial junctions, specifically in the diabetic peripheral vessels. These alterations may contribute to the increases in peripheral vascular permeability and endothelial dysfunction.