Effects of high glucose and pioglitazone on vascular responses in human saphenous vein

Objective: The long-term patency rate of grafts in coronary artery bypass grafting (CABG) surgery is low due to restenosis. Diabetes induces restenosis and vascular dysfunction leading to increased expression/activity of matrix metalloproteinases (MMPs) and oxidative stress formation. In our study, it was aimed to investigate the effects of high glucose on oxidative stress, expressions of MMP-2, MMP-9, MMP-14, TIMP-2 and vascular functional responses,and changes with pioglitazone in human saphenous vein (HSV) segments. Materials and Methods: HSV segments obtained from patients undergoing CABG were separated into 5 rings after the endothelium was gently removed. The rings were incubated in DMEM/F12 medium supplemented with 30mM glucose and/or 10mM pioglitazone or 0.1% DMSO for 24hrs. Untreated rings were called as controls. The levels of superoxide anion/reactive oxygen species (ROS) were examined by lucigenin/luminol chemiluminescence assay. MMP-2, MMP-9 expressions/activitieswere determined by gelatin zymography and MMP-14, TIMP-2 expressions were studied by immunohistochemistry. In the HSV rings, contractile responses to potassium chloride, noradrenaline, serotonin and prostaglandin F2α and relaxation responses to diltiazem and papaverine were performedby using an isolated organ bath system. Results: High glucose increased superoxide anion and ROS levels, but pioglitazone decreased the levels. Glucose increased MMP-2, MMP-14 expressions, MMP-2 activity, and decreased TIMP-2 expression. Pioglitazone inhibited MMP-2, MMP-14 expressions and MMP-2 activity, but increased TIMP-2.Glucose reduced responses to all contractile agents used but pioglitazone increased the responses in the HSV segments. Glucose reduced relaxation responses to diltiazem, but pioglitazone did not affect them. Papaverine responses were not affected by glucose or pioglitazone. Glucose decreased sensitivity to contractile agents, pioglitazone increased susceptibility to serotonin and prostaglandin F2α, but not to noradrenaline. Conclusion:Pioglitazone treatment may be useful for preventing early graft failure due to restenosis and for prolonged preservation of the functional performance of the graftin diabetic patients who have received HSV graft. Key Words: pioglitazone, high glucose, matrix metalloproteinases, oxidative stress, corronary artery bypass graft