Abstract 12454: Vildagliptin Attenuates Cardiac Hypertrophy and Improves Ventricular Efficiency Through FGF21 Expression in Pressure-overloaded Mouse Heart

Abstract

Introduction: Basic and clinical studies have shown that Dipeptidyl Peptidase-4 (DPP-4) inhibitor an anti-hyperglycemic agent, has cardioprotective effects through angiogenesis, anti-hypertrophy or anti-apoptosis effect. However, recent clinical trials in patients with diabetes raise a concern about DPP-4 inhibitor’s effect on heart failure. Based on the controversy, we performed precise analyses for cardiac energy metabolism and cardiac performance in hypertrophied heart induced by pressure-overload mouse model with or without diabetes. Methods and Results: Non-diabetic C57Bl6 mice (BL6) and type2 diabetic C57Bl6 mice produced by high fat diet (diet-induced obesity, DIO) were treated with or without a DPP-4 inhibitor, vildagliptin (VLD) after inducing pathological cardiac hypertrophy by transverse aortic constriction (TAC). After 3-week treatment, VLD attenuated cardiac hypertrophy and dysfunction compared with vehicle (Veh) treated animals in BL6. However these effects were not observed in DIO mice. Myocardial energy substrate assay using 12 C-FDG (glucose tracer) and 132 I-BMIPP (free fatty acid tracer) showed that not only glucose uptake but also free fatty acid uptake were increased with VLD treatment in TAC heart. Gene expression analysis showed that fibroblast growth factor (FGF) 21, a protein which has been shown to have a critical role in energy metabolism, was increased in heart with VLD treatment. In vitro experiments showed that VLD administration increased FGF21 expression dose-dependently in cultured human cardiac fibroblasts but not in neonatal cardiomyocytes, suggesting that fibroblast-mediated FGF21 expression may regulate energy metabolism in stressed heart. Conclusions: VLD has a beneficial effect on myocardial energy metabolism associating with an improvement of ventricular performance in hypertrophied heart, partially through upregulation of FGF21. However, these beneficial effects in heart may be attenuated under type2 diabetic condition.