title: Fenretinide inhibits macrophage inflammatory mediators and controls hypertension in spontaneously hypertensive rats via the peroxisome proliferator-activated receptor gamma pathway.
abstract: Fenretinide is a novel anticancer agent reported to exhibit anti-invasive and antimetastatic activities. It has also been shown to improve obesity and diabetes, although the effects of fenretinide on hypertension are still unknown, and the detailed mechanisms remain unclear. In this study, we have shown that treatment with lipopolysaccharide (LPS) decreased the expression of peroxisome proliferator-activated receptor γ (PPARγ) in RAW264.7 macrophages, and pretreatment with fenretinide reversed the effect of LPS on PPARγ expression. In addition, LPS-induced pro-inflammatory cytokine production, including tumor necrosis factor-α, interleukin 6, and monocyte chemoattractant protein 1 were dose-dependently reversed by fenretinide, and the effects of fenretinide on LPS-induced pro-inflammatory cytokine production were blocked by treatment with PPARγ antagonist. Moreover, fenretinide decreased LPS-induced inducible nitric oxide synthase expression and nitrogen oxide production. These effects were blocked by the pretreatment with PPARγ antagonist in a dose-dependent manner, indicating fenretinide activated PPARγ to exert anti-inflammation activity. In view of the role of inflammation in hypertension and the anti-inflammatory action of fenretinide, we found that administration of fenretinide in spontaneously hypertensive rats significantly decreased blood pressure. Taken together, these results indicate that fenretinide might be a potent antihypertensive agent that works by suppressing inflammation via activating PPARγ.
authors.affiliation: Department of Internal Medicine, Division of Endocrinology and Metabolism, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan.
authors.forename: Ching-Han
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Department of Internal Medicine, Division of Endocrinology and Metabolism, Chi-Mei Medical Center.
authors.forename: Shang-Yu
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Division of Holistic Care, Chi-Mei Medical Center.
authors.forename: Chun-Cheng
authors.initials: CC
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, Division of Endocrinology and Metabolism, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan.
authors.forename: Ye-Fong
authors.initials: YF
authors.lastname: Du
authors.affiliation: Department of Internal Medicine, Division of Endocrinology and Metabolism, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan.
authors.forename: Hao-Chang
authors.initials: HC
authors.lastname: Hung
authors.affiliation: Research Center of Clinical Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Hung-Tsung
authors.initials: HT
authors.lastname: Wu
authors.affiliation: Department of Internal Medicine, Division of Endocrinology and Metabolism, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan.
authors.forename: Horng-Yih
authors.initials: HY
authors.lastname: Ou
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D017313:Fenretinide / Q000494:pharmacology*; D006973:Hypertension / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D019402:Macrophage Inflammatory Proteins / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D000067996:RAW 264.7 Cells; D011918:Rats, Inbred SHR; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D000959:Antihypertensive Agents; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; D047495:PPAR gamma; D017313:Fenretinide; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse
keywords: fenretinide; hypertension; inflammation; macrophage; peroxisome proliferator-activated receptor γ