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.
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.
Authors: Laia Salvadó; Emma Barroso; Anna Maria Gómez-Foix; Xavier Palomer; Liliane Michalik; Walter Wahli; Manuel Vázquez-Carrera Journal: Diabetologia Date: 2014-07-26 Impact factor: 10.122
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Authors: Dominic K T Pang; Zengxuan Nong; Brian G Sutherland; Cynthia G Sawyez; Debra L Robson; Jelena Toma; J Geoffrey Pickering; Nica M Borradaile Journal: Pharmacol Res Perspect Date: 2016-04-14