Abstract 655: Dipeptidyl Peptidase-4 (dpp-4) Inhibition Decreases Cardiac And Vascular Stiffness And Improves Cardiac And Vascular Relaxation In Western Diet Fed Mice
A western diet (WD), high in sucrose and fat, is often accompanied by insulin resistance and cardiovascular disease characterized early by endothelial dysfunction and increased vascular and cardiac stiffness. Recently, Dipeptidyl peptidase-4 (DPP-4) inhibition has been shown to improve diastolic dysfunction in WD fed mice, but its effects on endothelial cell and cardiac stiffness have not been reported. We fed 4-week old C57BL/6 male mice with a WD with or without a DPP-4 inhibitor (MK0626) for 16 weeks and measured blood pressure by telemetry, insulin resistance via (HOMA), in vivo cardiac diastolic function (echocardiography), pulse wave velocity (PWV), and ex vivo aortic endothelial stiffness by atomic force microscopy. Systolic blood pressure and insulin resistance were increased by the WD. DPP-4 inhibition improved systemic insulin sensitivity and substantially reduced DPP-4 activity, but had no effect on 24-hour blood pressures. Heart weight was increased by WD in conjunction with S6 kinase translational signaling and DPP-4 inhibition reduced S6 kinase phosphorylation/activation in conjunction with a reduction in cardiac mass. Aortic stiffness, as assessed by PWV, was significantly increased in WD fed mice (16% increase) and was markedly decreased by DPP-4 inhibition. Endothelial cell stiffness was increased 5-fold in WD fed mice and DPP-4 inhibition significantly decreased endothelial stiffness (80% decrease). Acetylcholine but not sodium nitroprusside mediated vascular relaxation was impaired in WD fed mice and DPP-4 inhibition significantly improved this nitric oxide mediated relaxation. Increased vascular smooth muscle and endothelial stiffness was associated with impaired cardiac diastolic relaxation, which was also significantly improved by DPP-4 inhibition. Taken together, these results show that DPP-4 inhibition improves cardiac and vascular endothelial stiffness and cardiac diastolic dysfunction in a clinically translational mouse model (WD) of over nutrition and insulin resistance.
Author Disclosures: A.R. Aroor: None. V.G. DeMarco: None. G. Jia: None. L.A. Martinez-Lemus: None. J. Habibi: None. Z. Sun: None. M. Garro: None. G.A. Meininger: B. Research Grant (includes principal investigator, collaborator, or consultant and pending grants as well as grants already received); Modest; NIH 1P01HL095486. J.R. Sowers: B. Research Grant (includes principal investigator, collaborator, or consultant and pending grants as well as grants already received); Modest; NIH R01 HL073101, NIH R01 HL107910, VA Merit 0018.
- © 2014 by American Heart Association, Inc.