Dipeptidyl peptidase-4 inhibitor prevents the progression of heart failure after myocardial infarction in mice

Abstract

Background: Dipeptidyl peptidase-4 (DPP-4) inhibitors are newly available drugs for diabetes mellitus, but it is unclear whether DPP-4 inhibitors have cardioprotective effects or not. Methods: C57BL/6 mice and DPP-4 knockout (DPP-4-/-) mice were subjected to permanent ligation of left coronary artery. C57BL/6 mice were then treated with vehicle or DPP-4 inhibitor (MK-626, 3mg/kg/day). Left ventricular function was assessed using echocardiography at 5 days after acute myocardial infarction (MI). Infarct size, the number of vessels, and myocardial ischemia were assessed at 5 days after MI. The signal transduction pathways were analyzed by Western blot. Results: The treatment with DPP-4 inhibitor significantly improved fractional shortening (sham, 46.1±0.4%, control, 10.2±0.5%, MK, 14.0±0.4%, DPP-4-/-, 14.7±1.1%, p<0.05) and decreased the infarct size at 5 days after MI (control, 61.8±3.0%, MK, 43.6±1.5%, DPP-4-/-, 44.7±2.5%, p<0.05). DPP-4 inhibitor increased the ratio of endothelial cells to a cardiomyocyte (control, 0.92±0.06, MK, 1.24±0.01, DPP-4-/-, 1.30±0.04, p<0.05). The area of hypoxyprobe-1-positive myocardial ischemia in the border region was decreased by DPP-4 inhibition at 5 days after MI. The level of phosphorylated STAT3 was significantly increased by DPP-4 inhibition. These cardioprotective effects were also recognized after MI in DPP-4-/- mice. DPP-4 protein was expressed on rat neonatal cardiomyocytes. DPP-4 inhibitor significantly reduced hypoxia-induced apoptosis in the cardiomyocytes. However, this effect was abolished by the pretreatment with CXCR4 antagonist. Conclusion: DPP-4 inhibitors may have direct cardioprotective effects on the heart after MI by promoting survival signaling in cardiomyocytes and angiogenesis.