期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 34, 期 1, 页码 52-+出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.113.301830
关键词
atherosclerosis; inflammation; insulin resistance; lipids
资金
- Canadian Institutes of Health Research [MOP-126045]
- Heart and Stroke Foundation of Canada [PRG-5967]
- University of Western Ontario Department of Medicine (POEM)
- Ontario Graduate Scholarship
Objective-The peroxisome proliferator-activated receptor (PPAR) delta regulates systemic lipid homeostasis and inflammation. However, the ability of PPAR delta agonists to improve the pathology of pre-established lesions and whether PPAR delta activation is atheroprotective in the setting of insulin resistance have not been reported. Here, we examine whether intervention with a selective PPAR delta 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 alpha-actin was unchanged and collagen deposition enhanced. In aortae, GW1516 increased the expression of the PPAR delta-specific gene Adfp but not PPAR alpha- or gamma-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 PPAR delta agonist inhibits aortic inflammation and attenuates the progression of preestablished atherosclerosis.
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