Dipeptidyl Peptidase-4 Inhibition with Linagliptin Promotes Angiogenesis/Vasculogenesis in the Hearts of Female Diabetic db/db Mice

We have previously reported that the DPP-4 inhibitor linagliptin (LINA) prevents diastolic dysfunction and myocardial fibrosis in a mouse model of diet-induced obesity, a pre-clinical model of prediabetes. LINA suppressed WD-induced pro-inflammatory mediators, such as TRAF3IP2 and downstream signaling intermediates, NF-κB, AP-1 and p38-MAPK in the heart. Herein, we extend that study by testing whether LINA slows progression of diastolic dysfunction in diabetic db/db mice, and improves the underlying maladaptive immune/inflammatory response. To accomplish this, we fed db/db mice normal mouse chow with or without linagliptin (38 mg/kg chow). After performing echocardiography on mice treated or not for 10 weeks, we analyzed expression of 200 cytokines in myocardial extracts and performed Ingenuity Pathway Analysis (IPA) in an effort to determine what signaling pathways are predicted to be differentially activated in the heart. Mice treated with linagliptin had improved diastolic function indicated by lower LV filling pressure compared to untreated mice (E/E’; 35 vs. 50; p Disclosure R. Toedebusch: None. A.R. Aroor: None. J. Habibi: None. T. Klein: Employee; Self; Boehringer Ingelheim GmbH. L. Pulakat: None. V. DeMarco: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc..