过氧化物酶体增殖物激活受体 δ 激动剂 GW1516 可减轻载脂蛋白 E 基因敲除小鼠饮食诱导的主动脉炎症、胰岛素抵抗和动脉粥样硬化。
Peroxisome proliferator-activated receptor δ agonist GW1516 attenuates diet-induced aortic inflammation, insulin resistance, and atherosclerosis in low-density lipoprotein receptor knockout mice.
机构信息
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.
出版信息
Arterioscler Thromb Vasc Biol. 2014 Jan;34(1):52-60. doi: 10.1161/ATVBAHA.113.301830. Epub 2013 Oct 24.
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.
目的
过氧化物酶体增殖物激活受体 (PPAR) δ 调节全身脂质稳态和炎症。然而，PPARδ 激动剂改善已建立病变的病理的能力，以及 PPARδ 激活在胰岛素抵抗的情况下是否具有抗动脉粥样硬化作用尚未得到报道。在这里，我们研究了选择性 PPARδ 激动剂的干预是否可以纠正代谢失调并减轻主动脉炎症和动脉粥样硬化。
方法和结果
载脂蛋白 E 基因敲除小鼠喂食标准饮食或高脂肪、高胆固醇（HFHC）饮食（42%脂肪，0.2%胆固醇）4 周。在接下来的 8 周内，HFHC 组继续喂食 HFHC 或 HFHC 加 GW1516（每天 3mg/kg）。GW1516 显著减轻了已建立的空腹高脂血症、高血糖和高胰岛素血症以及葡萄糖和胰岛素不耐受。GW1516 干预明显减少主动脉窦病变和病变巨噬细胞，而平滑肌 α-肌动蛋白不变，胶原沉积增强。在主动脉中，GW1516 增加了 PPARδ 特异性基因 Adfp 的表达，但不增加 PPARα-或 γ-特异性基因的表达。GW1516 干预降低了主动脉前炎症性 M1 细胞因子的表达，增加了抗炎性 M2 细胞因子 Arg1 的表达，并降低了 iNos/Arg1 比值。已知体外增强炎症细胞因子表达的丝裂原活化蛋白激酶信号转导在 HFHC 喂养小鼠的主动脉中增强。此外，HFHC 饮食通过 Akt 和叉头框 O1 损害主动脉胰岛素信号转导，这与内质网应激标志物 CCAAT 增强子结合蛋白同源蛋白和 78kDa 葡萄糖调节蛋白的升高有关。GW1516 干预使丝裂原活化蛋白激酶激活、胰岛素信号转导和内质网应激正常化。
结论
PPARδ 激动剂的干预抑制主动脉炎症并减轻已建立的动脉粥样硬化的进展。
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