Abstract 11246: Antidiabetic Gliptins and G-csf Induce Cardiac Healing After Acute Myocardial Infarction in a Mouse Model

Abstract

Introduction: After myocardial infarction, loss of cardiomyocytes leads to ischemic cardiomyopathy and increased mortality. Usage of endogenous progenitor cell circulation may serve as new therapeutic option. Thus, we examined the effects of antidiabetic gliptins, which may stabilize the essential cardiac homing factor SDF-1 (stromal cell-derived factor), in combination with GCSF (granulocyte colony stimulating factor), which mobilizes bone-marrow derived stem cells, on cardiac regeneration after LAD ligation in a mouse model.

Methods and Results: By mass spectrometry, we verified that Sitagliptin/Vildagliptin administration per os lead to relevant blood levels. Activity of dipeptidylpeptidase (DPP) IV, which cleaves SDF-1, was sufficiently inhibited. GCSF or saline were administered intraperitoneally for 6 days. By stabilization of cardiac SDF1, Gliptins±GCSF administration increased mobilisation into peripheral blood as well as the myocardial homing of bone-marrow derived stem cells (assessed by flow cytometry). Furthermore, Sitagliptin, stimulated resident cardiac stem cells (CD34+CD45+ckit+ and CD34+CD45+Sca1+) and increased neovascularization (CD31+ cells) as well as cell proliferation (Ki67+ cells in histological analyses). Additionally, cardiac expression of microRNA 21, 155 and 126 (assessed by RT-PCR) were reduced in the infarct zone after Sitagliptin+GCSF administration. Infarct areas were decreased in analogy. These effects in combination enhanced myocardial function (millar-tip catheterization) and improved survival for both gliptins±GCSF (Kaplan-Meier curve, n=20 in each group). Gliptins as a mono therapy showed relevant effects dose dependently. However, combined therapy with gliptins and GCSF showed the best effects. There seems to be a class-effect of DPP-IV inhibitors, because both gliptins revealed comparable results concerning cardiac stem cell homing, heart function and mortality.

Conclusion: Gliptins+GCSF and in high concentrations even as mono therapy show remarkable effects on cardiac healing after myocardial infarction beyond its anti-diabetic potential.