Abstract | OBJECTIVE: METHODS AND RESULTS: Serum concentrations of GIP were assessed in 731 patients who presented for elective coronary angiography at the University Hospital Aachen. While GIP concentrations were not associated with coronary artery disease (CAD), we found 97 patients with PAD ( peripheral artery disease) vs. 634 without PAD to have higher circulating GIP levels (413.0 ± 315.3 vs. 332.7 ± 292.5 pg/mL, p = 0.0165). GIP levels were independently related to PAD after multivariable adjustment for CAD, age, sex, BMI, hypertension, diabetes, CRP, WBC, and smoking. To investigate the functional relevance of elevated GIP levels in human atherosclerotic disease, we overexpressed GIP (1-42) in ApoE-/- mice fed a Western diet for 12 weeks using an adeno-associated viral vector system. GIP overexpression led to reduced atherosclerotic plaque macrophage infiltration and increased collagen content compared to control (LacZ) with no change in overall lesion size, suggesting improved plaque stability. Mechanistically, we found GIP treatment to reduce MCP-1-induced monocyte migration under In vitro conditions. Additionally, GIP prevented proinflammatory macrophage activation leading to reduced LPS-induced IL-6 secretion and inhibition of MMP-9 activity, which was attributable to GIP dependent inhibition of NfκB, JNK-, ERK, and p38 in endotoxin activated macrophages. CONCLUSION: Elevated concentrations of the incretin hormone GIP are found in patients with atherosclerotic cardiovascular disease, while GIP treatment attenuates atherosclerotic plaque inflammation in mice and abrogates inflammatory macrophage activation in vitro. These observations identified GIP as a counterregulatory vasoprotective peptide, which might open new therapeutic avenues for the treatment of patients with high cardiovascular risk.
|
Authors | Florian Kahles, Ana Liberman, Constantin Halim, Matthias Rau, Julia Möllmann, Robert Werner Mertens, Marcia Rückbeil, Irmgard Diepolder, Benedikt Walla, Sebastian Diebold, Mathias Burgmaier, Corinna Lebherz, Nikolaus Marx, Michael Lehrke |
Journal | Molecular metabolism
(Mol Metab)
Vol. 14
Pg. 150-157
(08 2018)
ISSN: 2212-8778 [Electronic] Germany |
PMID | 29884547
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Copyright | Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved. |
Chemical References |
- Apolipoproteins E
- Gastric Inhibitory Polypeptide
|
Topics |
- Aged
- Animals
- Apolipoproteins E
(genetics)
- Atherosclerosis
(blood)
- Female
- Gastric Inhibitory Polypeptide
(blood, therapeutic use)
- Humans
- Macrophage Activation
- Male
- Mice
- Mice, Inbred C57BL
- Middle Aged
- Plaque, Atherosclerotic
(blood, drug therapy)
- RAW 264.7 Cells
- Up-Regulation
|