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Background: Recent study suggested that DPP4 inhibition has a direct, GLP-1 independent, effect on the progression of diabetic nephropathy via interaction with integrin β1. We compared the effects of no treatment, linagliptin (Lina, a DPP4 inhibitor) and direct GLP-1 receptor activation by exenatide followed by exendin-4 in an infusion pump (EX) on infarct size (IS) and post-infarction activation of the inflammasome in wild type (WT), nondiabetic mice and in db/db mice with type-2 diabetes.
Methods: Mice underwent 30 min coronary artery occlusion followed by reperfusion. IS was assessed by tetrazolium tetrachloride at 24h of reperfusion. Cardiac function was assessed by echocardiography 2 weeks after infarction. Activation of the inflammasome in the border zone of the infarction was assessed by rt-PCR 2 weeks after reperfusion.
Results: Lina and EX limited IS in both the WT (23±2% and 32±3% vs. 50±3%) and the db/db mice (29±2% and 29±2% vs. 53±2%). IS tended to be smaller with Lina than with EX in the WT (p=0.055), but not the db/db mice. Left ventricular ejection fraction was reduced by infarction (56±1% vs. 81±1% in the WT and 50±1% vs. 78±1% in the db/db mice). Lina and EX improved LVEF without a difference between Lina and EX in both the WT (73±1% and 73±2% vs. 50±3% in the controls) and the db/db (68±1% and 66±2% vs. 53±2% in the controls) mice. Messenger RNA (mRNA) levels of ASC, NALP3, IL-1β, IL-6, Collagen-1 and Collagen-3 were higher in the db/db mice than in the WT mice. Myocardial infarction increased these levels in the WT and db/db mice. Lina more than Ex attenuated the increase in ASC, NALP3, IL-1β, IL-6, Collagen-1 and Collagen-3, especially in the db/db mice.
Conclusions: Lina and EX had similar effects on IS and post-infarction function, but DPP-4 inhibition with Lina attenuated the activation of the inflammasome and the upregulation of collagen-1 and −3 more than direct GLP-1 receptor activation by EX.
Poster Hall, Hall C
Saturday, March 18, 2017, 3:45 p.m.-4:30 p.m.
Session Title: Emerging Basic Science in Ischemic Heart Disease
Abstract Category: 1. Acute and Stable Ischemic Heart Disease: Basic
Presentation Number: 1251-299
- 2017 American College of Cardiology Foundation