464-P: Linagliptin Directly Enhances Cardiac Contractile Recovery through Nitric Oxide Mediated Endothelial–Cardiomyocyte Communication

Abstract

Despite a similar mechanism of action underlying their glucose-lowering effects, dipeptidyl peptidase-4 (DPP-4) inhibitors have diverse molecular structures, raising the prospect of agent-specific, glucose-independent actions. This possibility is supported by heterogeneous heart failure outcomes in cardiovascular trials, although few head-to-head comparisons exist. To explore the possibility of DPP-4 inhibitor cardiac heterogeneity, we perfused mouse hearts with different DPP-4 inhibitors at concentrations equivalent to their peak plasma levels achieved in humans with standard dosing (Cmax). We studied male and female mice, young nondiabetic mice and aged diabetic high fat diet-fed mice and observed that linagliptin enhanced recovery after ischemia-reperfusion, whereas sitagliptin, alogliptin and saxagliptin did not. DPP-4 transcripts were not detected in adult mouse cardiomyocytes by RNA-sequencing and the addition of linagliptin caused ≤0.2% of cardiomyocyte genes to be differentially expressed. In contrast, incubation of C166 endothelial cells with linagliptin induced cell signaling characterized by phosphorylation of Akt and endothelial nitric oxide synthase, whereas the nitric oxide (NO) donor, S-nitroso-N-acetylpenicillamine increased serine 16 phosphorylation of the calcium regulatory protein, phospholamban in cardiomyocytes. Thus, at concentrations achieved with standard dosing in humans, linagliptin has direct effects on the recovery of mouse cardiac contractility after ischemia-reperfusion, most likely through NO-mediated endothelial-cardiomyocyte communication. The complex cardiac actions of NO (that depend on comorbidity, concurrent medications and disease setting, for instance) may contribute to both the discordance in DPP-4 inhibitor outcomes between preclinical and clinical observations and the heterogeneous outcomes observed in clinical trials to date. Disclosure V. Yerra: None. S. Batchu: None. Y. Liu: None. T. Klein: Employee; Self; Boehringer Ingelheim International GmbH. A. Advani: Research Support; Self; Boehringer Ingelheim International GmbH. Funding Boehringer Ingelheim