In:
Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 130, No. suppl_2 ( 2014-11-25)
Abstract:
Background: We demonstrated that dipeptidyl-peptidase-4 inhibitor (DPP4i) Des-Fluoro-Sitagliptin (DFS) exhibited anti-atherosclerotic effects on the newly development process of atherosclerosis, however it is unknown whether DPP4i also have anti-atherosclerotic effects on the established atheroma (preventing progression or regression). In the practical situation, it is clinically important to investigate whether DPP4i have beneficial effects on the established atherosclerosis. Methods and Results: 8 weeks old ApoE deficient mice were fed by high fat diet (HFD) for 12 weeks lead to development of the established atherosclerotic plaques, followed by randomized into 4 groups; continued HFD arm [HFD alone, HFD+DFS (200mg/kg/day)] and lipid-lowering arm [low fat diet (LFD) alone, LFD+DFS] , for additional 8 weeks. DFS significantly reduced the progression of established plaque compared to HFD alone [plaque area per aorta; HFD (n=11): 53.3±4.9% vs. HFD+DFS (n=15): 43.8±9.0%, p 〈 0.05]. During the lipid-lowering therapy by diet, DFS supported the diet-induced regression of atherosclerosis [baseline 20 weeks old (n=10): 34.6±11.4%, LFD (n=17): 32.7±7.8% vs. LFD+DFS (n=18): 30.2±9.1%] . In vitro, DFS with glucagon-like peptide-1 (GLP-1) increased the phosphorylation of AMPK in human coronary artery endothelial cells (HCAEC) (2.71±0.31 fold, p 〈 0.01) and in THP-1-drived human macrophages (1.29±0.07 fold, p 〈 0.05). DFS with GLP-1 reduced the expression of adhesion molecules induced by tissue necrosis factor-α (intercellular adhesion molecule-1: -18.1±2.6%, p 〈 0.05, vascular cell adhesion molecule-1: -22.4±4.5%, p 〈 0.05), and these effects were abolished by AMPK inhibitor (Compound-C; CC) in HCAEC. In macrophages, DFS with GLP-1 reduced expression of the M1 pro-inflammatory factor (interleukin (IL)-1β; 0.74±0.04 fold, p 〈 0.05) but not the M2 anti-inflammatory factor (IL-10; 1.00±0.06 fold, p=0.99) and the effect on M1 was abolished by CC. Conclution: DFS exhibited beneficial effects on the established atherosclerosis with attenuating progression and supporting regression by the lipid-lowering therapy. AMPK activation by DFS might partly play a role in these processes. DFS could also be effective for the established atherosclerosis.
Type of Medium:
Online Resource
ISSN:
0009-7322
,
1524-4539
DOI:
10.1161/circ.130.suppl_2.13760
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2014
detail.hit.zdb_id:
1466401-X
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