Dipeptidyl Peptidase-4 Inhibition Improves Cardiac Function In Experimental Myocardial Infarction: Role Of Stromal Cell-Derived Factor-1 Alpha

BackgroundIn addition to degrading glucagon-like peptide-1 (GLP-1), dipeptidyl peptidase-4 (DPP-4) inactivates several chemokines, including stromal cell-derived factor-1 (SDF-1), a pro-angiogenic and cardiomyocyte protective protein. We hypothesized that DPP-4 inhibition may confer benefit following myocardial infarction (MI) in the diabetic setting as a consequence of enhanced SDF-1 availability rather than potentiating GLP-1. To test this we compared the effects of saxagliptin with those of liraglutide and used the SDF-1 receptor (CXCR4) antagonist plerixafor.MethodsStudies were conducted in streptozotocin-diabetic rats. Rats were randomized to receive saxagliptin (10mg/kg per day), liraglutide (0.2mg/kg, s.c., b.i.d.), plerixafor (1mg/kg per day, s.c.), saxagliptin plus plerixafor or vehicle (1% phosphate-buffered saline). Two weeks later, rats underwent experimental MI, with cardiac function examined 4 weeks after MI.ResultsGlycemic control and MI size were similar in all groups. Four weeks after MI, mortality was reduced in saxagliptin-treated rats compared with vehicle treatment (P<0.05). Furthermore, rats receiving saxagliptin had improved cardiac function compared with vehicle-treated rats (P<0.05). Antagonism of CXCR4 prevented the improvement in cardiac function in saxagliptin-treated rats and was associated with increased mortality (P<0.05).ConclusionSaxagliptin-mediated DPP-4 inhibition, but not liraglutide-mediated GLP-1R agonism, improved cardiac function after MI independent of glucose lowering. These findings suggest that non-GLP-1 actions of DPP-4 inhibition, such as SDF-1 potentiation, mediate biological effects.