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<0.05). IPA predicted that LINA activates pathways contributing to cardiovascular development of the vasculature (32 molecules, Activiation z-score = 3.7), angiogenesis (31 molecules, Activation z-score = 3.7) and vasculogenesis (27 molecules, Activation z-score = 3.7). Cardiomyocyte size (i.e., cross-sectional area) was reduced by 23% (533±30 vs. 411±18 μm2; p<0.05) and myocardial capillary density was two-fold higher with LINA treatment compared to untreated mice (p<0.05). In addition, the proteome analysis showed a significant decrease in TNF-α related apoptosis inducing ligand, a cytokine that induces endothelial nitric oxide, in untreated mice, however, this deficiency was prevented by LINA. These data suggest that linagliptin exerts a beneficial immune/inflammatory response in the diabetic heart that confers myocardial vasculoprotection.
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..