Diabetes mellitus (DM) is one of the leading causes of morbidity and mortality worldwide.1 DM is a major and independent risk factor for many life-threatening cardiovascular (CV) complications such as coronary artery disease (CAD), stroke, and heart failure. 2., 3., 4. CAD which is the most prevalent CV complication in DM patients requires a special attention in the management of DM.2., 3. Prolonged hyperglycemia triggers production of reactive oxygen species (ROS), and inflammatory processes stimulated by excessive release of cytokines/growth factors, and activation of matrix metalloproteinases (MMPs), leading to vascular dysfunction, vascular smooth muscle cell (VSMC) proliferation and migration, and ultimately to intimal hyperplasia in coronary arteries.5., 6., 7., 8., 9. This early stage is followed by plaque formation and restenosis. MMPs play major role in restenosis by inducing VSMC proliferation/migration and in accelerated atherosclerosis syndromes by making plaques vulnerable to rupture.10., 11.

CABG surgery has shown to be superior to drug-eluting stenting in reducing the risk of acute coronary events and death in DM patients.12 Human saphenous vein graft (HSV) is the most widely used conduit in CABG surgery.13., 14. However, inflammatory processes triggered in the HSV graft cause vascular dysfunction in early phase and restenosis extending to graft failure in long term, thus they limit the success of CABG surgery.14 In patients undergoing CABG surgery DM expedites this process, deteriorate clinical outcomes and increases mortality rates compared to nondiabetic ones.15., 16.

Recent clinical trials report that the effects of oral antidiabetic agents on the prevention of CAD-related acute coronary syndromes are insufficient or mostly uncertain.3 However, several meta-analyses and database analyses revealed that pioglitazone, a thiazolidinedione (TZD) class antidiabetic drug, exerts beneficial effects by reducing the risk of coronary restenosis and cardiovascular events.17., 18. Furthermore, pioglitazone was shown to have pleiotropic effects such as inhibition of VSMC proliferation/migration and inflammatory cytokine synthesis and dyslipidemia in some experimental atherosclerosis models.19., 20., 21., 22., 23. Nevertheless, the effects of pioglitazone on oxidative stress, MMPs, MMP inhibitors (TIMPs), VSMC proliferation and vascular function in a standard diabetic HSV graft model have not been studied yet.

In the present study, to establish whether pioglitazone may prevent the acute CV events related restenosis in HSV grafts of DM patients underwent CABG operation, an ex vivo standard diabetic HSV graft model was constructed by incubating HSV grafts with a standard high-concentration of glucose (30 mM) for 24 h, and the effects of pioglitazone on ROS levels, expressions/activities of MMPs and TIMP-2, VSMC proliferation and vascular reactivity were investigated in the same HSV graft.