Sitagliptin, a dipeptidyl peptidase-4 inhibitor, attenuates apoptosis of vascular smooth muscle cells and reduces atherosclerosis in diabetic apolipoprotein E-deficient mice

Sitagliptin, a dipeptidyl peptidase-4(DPP-4) Inhibitor, has been found to have an anti-atherosclerotic effect. Since apoptosis of vascular smooth muscle cells (VSMCs) contributes to the occurrence of diabetic atherosclerosis. This study aimed to examine whether sitagliptin suppresses the atherosclerosis progression to hyperglycemia in a low-dose streptozotocin (STZ)-induced diabetic mouse model, and then investigated the effect of sitagliptin on VSMCs apoptosis and its underlying mechanism. In vivo studies, eight-week-old low-dose STZ-induced diabetic apolipoprotein E (apoE)-deficient (apoE-/-) mice fed a high-fat diet were administered a DPP-4 inhibitor, sitagliptin, 200 mg/kg/day, or Lantus insulin by daily subcutaneous injection of 1 unit/mouse over a period of 12 weeks. Aortic atherosclerosis and apoptosis in the plaque were determined using dUTP-biotin nick end labeling (TUNEL) staining and immunohistochemistry. In vitro studies utilized the VSMCs for determination of glucagon-like peptide 1 receptor (GLP-1R) and DPP-4 expression and flow cytometry and Western blotting were used to determine apoptosis and protein expression, respectively. Sitagliptin significantly reduced atherosclerotic lesion area (7.00 +/- 0.13 vs. 12.80 +/- 2.7%, p = 0.003) and suppressed vascular smooth muscle cell apoptosis (2.30 +/- 1.34 vs. 4.8 +/- 1.93%, p = 0.003) compared with vehicle treatment. In addition, sitagliptin significantly increased the expression of beta-catenin in the aortic tissue(0.56 +/- 0.13 vs.0.17 +/- 0.02, p = 0.008)compared with vehicle treatment. In cultured mouse VSMCs, sitagliptin enhanced GLP-1 activity significantly retarded oxidative stress (H2O2)-induced apoptosis compared with GLP-1 or sitagliptin alone. Sitagliptin increased GLP-1-induced cytosolic levels of beta-catenin compared with GLP-1 alone, resulted in increasing the expression of survivin, and suppressed proinflammatory cytokines, i.e., interleukin-6(IL-6) and tumor necrosis factor-alpha(TNF-alpha), production in response to H2O2. In conclusion, these results indicated that the anti-atherosclerotic effect of sitagliptin is mediated, at least in part, by its inhibition of VSMCs apoptosis.

Automated summary

Sitagliptin significantly reduces atherosclerotic lesion area, suppresses vascular smooth muscle cell apoptosis, and increases the expression of beta-catenin in aortic tissue. In vitro, sitagliptin enhances GLP-1 activity, retards oxidative stress-induced apoptosis, and suppresses the production of inflammatory cytokines.