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Arterioscler Thromb Vasc Biol. 2014 Jan;34(1):52-60. doi: 10.1161/ATVBAHA.113.301830. Epub 2013 Oct 24.

Peroxisome proliferator-activated receptor δ agonist GW1516 attenuates diet-induced aortic inflammation, insulin resistance, and atherosclerosis in low-density lipoprotein receptor knockout mice.

Author information

1
From the Department of Vascular Biology, Robarts Research Institute (L.A.B., A.C.B., S.S.C., D.E.T., B.G.S., J.Y.E., C.G.S., H.Y., J.G.P., M.W.H.), London, Ontario, Canada; and Departments of Biochemistry (L.A.B., A.C.B., S.S.C., J.G.P., M.W.H.), Medicine (D.E.T., J.Y.E., C.G.S., R.G.T., J.G.P., M.W.H.), and Physiology and Pharmacology (R.G.T.), The University of Western Ontario, London, Ontario, Canada.

Abstract

OBJECTIVE:

The peroxisome proliferator-activated receptor (PPAR) δ regulates systemic lipid homeostasis and inflammation. However, the ability of PPARδ agonists to improve the pathology of pre-established lesions and whether PPARδ activation is atheroprotective in the setting of insulin resistance have not been reported. Here, we examine whether intervention with a selective PPARδ agonist corrects metabolic dysregulation and attenuates aortic inflammation and atherosclerosis.

APPROACH AND RESULTS:

Low-density lipoprotein receptor knockout mice were fed a chow or a high-fat, high-cholesterol (HFHC) diet (42% fat, 0.2% cholesterol) for 4 weeks. For a further 8 weeks, the HFHC group was fed either HFHC or HFHC plus GW1516 (3 mg/kg per day). GW1516 significantly attenuated pre-established fasting hyperlipidemia, hyperglycemia, and hyperinsulinemia, as well as glucose and insulin intolerance. GW1516 intervention markedly reduced aortic sinus lesions and lesion macrophages, whereas smooth muscle α-actin was unchanged and collagen deposition enhanced. In aortae, GW1516 increased the expression of the PPARδ-specific gene Adfp but not PPARα- or γ-specific genes. GW1516 intervention decreased the expression of aortic proinflammatory M1 cytokines, increased the expression of the anti-inflammatory M2 cytokine Arg1, and attenuated the iNos/Arg1 ratio. Enhanced mitogen-activated protein kinase signaling, known to induce inflammatory cytokine expression in vitro, was enhanced in aortae of HFHC-fed mice. Furthermore, the HFHC diet impaired aortic insulin signaling through Akt and forkhead box O1, which was associated with elevated endoplasmic reticulum stress markers CCAAT-enhancer-binding protein homologous protein and 78kDa glucose regulated protein. GW1516 intervention normalized mitogen-activated protein kinase activation, insulin signaling, and endoplasmic reticulum stress.

CONCLUSIONS:

Intervention with a PPARδ agonist inhibits aortic inflammation and attenuates the progression of pre-established atherosclerosis.

KEYWORDS:

atherosclerosis; inflammation; insulin resistance; lipids

PMID:
24158519
DOI:
10.1161/ATVBAHA.113.301830
[Indexed for MEDLINE]

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