Abstract 11421: Dipeptidyl Peptidase-4 Inhibitor Prevents the Progression of Heart Failure After Myocardial Infarction
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 left coronary artery ligation. 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 number of TUNEL-positive cells was assessed at 3 days after MI. SDF-1α concentration in myocardium was evaluated by ELISA at 3 days after MI. We performed Western blot analysis and immunocytochemistry in cultured rat neonatal cardiomyocytes.
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%, p<0.05) and significantly decreased the infarct size at 5 days after MI (control, 61.8±3.0%, MK, 43.6±1.5%, p<0.05). DPP-4 inhibitor increased the ratio of endothelial cell numbers to a cardiomyocyte (control, 0.92±0.06, MK, 1.24±0.01, p<0.05), and decreased the area of hypoxyprobe-1-positive myocardial ischemia in the border region (control, 12.2±2.6, MK, 4.5±1.7, p<0.05). The number of TUNEL-positive cells in the border region was significantly decreased by DPP-4 inhibition. SDF-1 level was significantly increased in MI mice compared to Sham mice (control, 20.5±0.9, MK, 22.6±0.3, p<0.05), and in MI mice, SDF-1α level in myocardium was significantly increased by DPP-4 inhibition (control, 40.4±2.0, MK, 50.8±3.2, p<0.05). These cardioprotective effects were also recognized after MI in DPP-4-/- mice. DPP-4 protein was expressed on rat neonatal cardiomyocytes, and DPP-4 inhibitor ignificantly reduced hypoxia-induced apoptosis in the cardiomyocytes. However, this effect was abolished by the pretreatment with AMD3100, CXCR4 antagonist.
Conclusion: DPP-4 inhibitors may have direct cardioprotective effects on the heart after MI by promoting antiapoptotic effect and angiogenesis through SDF-1/CXCR4-mediated signaling pathway.
- © 2013 by American Heart Association, Inc.