Glucose-Dependent Insulinotropic Polypeptide (GIP) Stimulates Osteopontin Expression in the Vasculature via Endothelin-1 and CREB

Lisa M Berglund, Valeriya Lyssenko, Claes Ladenvall, Olga Kotova, Andreas Edsfeldt, Kasper Pilgaard, Sami Alkayyali, Charlotte Brøns, Carol Forsblom, Anna Jonsson, Anna V Zetterqvist, Mihaela Nitulescu, Christian Ruiz McDavitt, Pontus Dunér, Alena Stancáková, Johanna Kuusisto, Emma Ahlqvist, Maria Lajer, Lise Tarnow, Sten MadsbadPeter Rossing, Timothy J Kieffer, Olle Melander, Marju Orho-Melander, Peter Nilsson, Per-Henrik Groop, Allan Vaag, Bengt Lindblad, Anders Gottsäter, Markku Laakso, Isabel Goncalves, Leif Groop, Maria F Gomez

37 Citationer (Scopus)

Abstract

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone with extrapancreatic effects beyond glycemic control. Here we demonstrate unexpected effects of GIP signaling in the vasculature. GIP induces the expression of the pro-atherogenic cytokine osteopontin (OPN) in mouse arteries, via local release of endothelin-1 (ET-1) and activation of cAMP response element binding protein (CREB). Infusion of GIP increases plasma OPN levels in healthy individuals. Plasma ET-1 and OPN levels are positively correlated in patients with critical limb ischemia. Fasting GIP levels are higher in individuals with a history of cardiovascular disease (myocardial infarction, stroke) when compared to controls. GIP receptor (GIPR) and OPN mRNA levels are higher in carotid endarterectomies from patients with symptoms (stroke, transient ischemic attacks, amaurosis fugax) than in asymptomatic patients; and expression associates to parameters characteristic of unstable and inflammatory plaques (increased lipid accumulation, macrophage infiltration and reduced smooth muscle cell content). While GIPR expression is predominantly endothelial in healthy arteries from human, mouse, rat and pig; remarkable up-regulation is observed in endothelial and smooth muscle cells upon culture conditions yielding a "vascular disease-like" phenotype. Moreover, a common variant rs10423928 in the GIPR gene associated with increased risk of stroke in type 2 diabetes patients.

OriginalsprogEngelsk
TidsskriftDiabetes
Vol/bind65
Udgave nummer1
Sider (fra-til)239-254
ISSN0012-1797
DOI
StatusUdgivet - 2016

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