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

Abstract

Objectives We investigated the changes in adherens-junction-proteins, such as vascular endothelial (VE)-cadherin and β-catenin of skeletal muscle and vessels in patients with or without diabetes in the setting of CPB and cardiac surgery. Methods Skeletal muscle tissue samples were harvested pre- and post-CPB from non-diabetic (ND) (HgbA1c: 5.4 ± 0.1), controlled diabetic (CDM) (HgbA1c: 6.3 ± 0.1), and uncontrolled diabetic patients (UDM) (HgbA1c: 9.6 ± 0.3) undergoing CABG surgery (n = 8/group). The expression/phosphorylation of adherens-junction-proteins VE-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 VE-cadherin was not changed at baseline or between pre- and post-CPB among groups. The pre-CPB level of phospho-VE-cadherin was found to be significantly increased in the UDM group compared with the ND or CDM groups (P <0.05). The post-CPB levels of phospho-VE-cadherin were significantly increased as compared with pre-CPB in all groups (P <0.05 each), and this increase was greater in the UDM group than that of the ND or CDM groups (P<0.05). Expression of basal β-catenin protein in UDM group was decreased as compared with ND or CDM (P<0.05). There were significant decreases in the β-catenin protein expression between pre- and post-CPB in all three groups (P<0.05 each) and this decrease was greater in the UDM group than the ND group (P<0.05). There were decreases in the relaxation response of skeletal muscle arterioles to substance P after CPB in all three groups (P<0.05), and this alteration was more pronounced in the UDM patients (P<0.05). Conclusion Uncontrolled diabetes causes inactivation and reduction in the expression of endothelial adherens-junction-protein in the arterioles of skeletal muscle early after CPB. The enhanced phosphorylation of VE-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.

Influence of the Acute Inflammation and Endothelial Dysfunction on the Retinal Vein Occlusion Formation After Cardio-Surgical Interferences With the Use of Cardiopulmonary Bypass

“…The cascade of inflammatory reactions leads to damage of the vascular endothelium and contributes to the progression of ischemia, thrombosis, macrophages activation [18]. The regression analysis shows that the content of VE-C after 8 days is important for the development of RVO, what is compliant with the literature data and reflects the development and pathogenetic value of EDF [19,20].…”

Inflammation but not Glycemic Control is Associated with Neurocognitive Decline After Cardiac Surgery

“…[17][18][19][20] Marked alterations in vasomotor regulation have been documented after cardiac surgery utilizing cardiopulmonary bypass both in vivo 21 and in vitro. [17][18][19][20]22,23 These changes in vasomotor regulation and other cellular signaling are exacerbated or different in patients with poorly controlled diabetes compared to patients without diabetes or well controlled diabetes. [22][23][24][25] While hyperglycemia is often seen as an inflammatory state and therefore theorized to be associated with inflammatory markers penetrating the blood-brain barrier and causing decreased neurocognitive function, we did not observe that in this study.…”

“…[17][18][19][20]22,23 These changes in vasomotor regulation and other cellular signaling are exacerbated or different in patients with poorly controlled diabetes compared to patients without diabetes or well controlled diabetes. [22][23][24][25] While hyperglycemia is often seen as an inflammatory state and therefore theorized to be associated with inflammatory markers penetrating the blood-brain barrier and causing decreased neurocognitive function, we did not observe that in this study. Neither did pre-existing diabetes, as determined by an elevated preoperative HbA1c level, nor elevations of glucose levels the morning of or intra-operatively have any effect on early neurocognitive function.…”

Cyclooxygenase 2 contributes to bradykinin-induced microvascular responses in peripheral arterioles after cardiopulmonary bypass

“…It has been well recognized that bradykinin induced vascular relaxation is endothelium-dependent. 17–19 A sub-group of arterioles was also treated with a COX-2 inhibitor NS398 (10 −5 M) before the exposure to bradykinin for analysis of the effect of COX-2 on this vasodilation pathway.…”