O45-3 - Dpp4 Inhibitor Attenuates Cardiac Systolic Dysfunction in a Murine Dietary Obese Model by Promoting Fibroblast Growth Factor 2-mediated Angiogenesis

Abstract

Dipeptidyl peptidase-4 (Dpp4) inhibitors are used worldwide to combat diabetes, however, their roles in cardiovascular disorders are yet to be defined. Here we show that a DPP4 inhibitor, linagliptin, contributes for the suppression of capillary rarefaction in diabetic heart and systolic dysfunction. The capillary rarefaction in dietary obese mice associated with high DPP4 level in circulation, and the administration of linagliptin suppressed the development of capillary rarefaction and ameliorated cardiac dysfunction. DNA micro array data showed that early growth response protein 1 (EGR1), known as an angiogenic transcription factor, is significantly reduced in the cardiac tissue upon metabolic stress, and this suppression was inhibited by the administration of linagliptin. Fibroblast growth factor 2 (FGF-2) has putative amino acid sequence cleaved by DPP4, and LC-MS/MS studies showed that DPP4 actually cleaves FGF-2. In vitro studies showed that FGF-2 contributes to up-regulation of Egr1 expression, and this was suppressed with DPP4. Furthermore, our studies suggested that vascular endothelial growth factor a (VEGFa) is the critical angiogenic factor mediating FGF-2-EGR-1 signaling. Our studies suggest that DPP4 inhibits FGF-2/EGR-1/VEGFa signaling in cardiac tissues. Suppression of DPP4 is crucial for the suppression of capillary rarefaction and cardiac dysfunction in diabetic heart.