title: Palmitic acid increases pro-oxidant adaptor protein p66Shc expression and affects vascularization factors in angiogenic mononuclear cells: Action of resveratrol.
abstract: A defect in neo-vascularization process involving circulating angiogenic mononuclear cells (CACs) dysfunction is associated with diabetes. We showed that oxidative stress was elevated in CACs cultured from blood of individuals with metabolic syndrome (MetS) and diabetes. We then assessed the action of palmitic acid (PA), a deregulated and increased NEFA in metabolic disorders, focusing on its oxidant potential. We observed that the phyto-polyphenol resveratrol normalized oxidative stress both in CACs isolated from MetS patients or treated with PA. Resveratrol further decreased the deleterious action of PA on gene expression of vascularization factors (TNFα, VEGF-A, SDF1α, PECAM-1, VEGFR2, Tie2 and CXCR4) and improved CAC motility. Particularly, resveratrol abolished the PA-induced over-expression of the pro-oxidant protein p66Shc. Neither KLF2 nor SIRT1, previously shown in resveratrol and p66Shc action, was directly involved. Silencing p66Shc normalized PA action on VEGF-A and TNFα specifically, without abolishing the PA-induced oxidative stress, which suggests a deleterious role of p66Shc independently of any major modulation of the cellular oxidative status in a high NEFA levels context. Besides showing that resveratrol reverses PA-induced harmful effects on human CAC function, certainly through profound cellular modifications, we establish p66Shc as a major therapeutic target in metabolic disorders, independent from glycemic control.
authors.affiliation: Department of Molecular Cell Biology, VU University Medical Center, van der Boechorstraat 7, 1081BT Amsterdam, The Netherlands.
authors.forename: Julie
authors.initials: J
authors.lastname: Favre
authors.affiliation: Department of Molecular Cell Biology, VU University Medical Center, van der Boechorstraat 7, 1081BT Amsterdam, The Netherlands.
authors.forename: Cansu
authors.initials: C
authors.lastname: Yildirim
authors.affiliation: Department of Molecular Cell Biology, VU University Medical Center, van der Boechorstraat 7, 1081BT Amsterdam, The Netherlands.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Leyen
authors.affiliation: Department of Diabetes Center Internal medicine, VU University Medical Center, van der Boechorstraat 7, 1081BT Amsterdam, The Netherlands.
authors.forename: Weena J Y
authors.initials: WJ
authors.lastname: Chen
authors.affiliation: Department of Diabetes Center Internal medicine, VU University Medical Center, van der Boechorstraat 7, 1081BT Amsterdam, The Netherlands.
authors.forename: Renate E
authors.initials: RE
authors.lastname: van Genugten
authors.affiliation: Department of Diabetes Center Internal medicine, VU University Medical Center, van der Boechorstraat 7, 1081BT Amsterdam, The Netherlands.
authors.forename: Larissa W
authors.initials: LW
authors.lastname: van Golen
authors.affiliation: Department of Molecular Cell Biology, VU University Medical Center, van der Boechorstraat 7, 1081BT Amsterdam, The Netherlands.
authors.forename: Juan-Jesus
authors.initials: JJ
authors.lastname: Garcia-Vallejo
authors.affiliation: Department of Physiology, VU University Medical Center, van der Boechorstraat 7, 1081BT Amsterdam, The Netherlands.
authors.forename: Rene
authors.initials: R
authors.lastname: Musters
authors.affiliation: Department of Molecular Cell Biology, VU University Medical Center, van der Boechorstraat 7, 1081BT Amsterdam, The Netherlands.
authors.forename: Josefien
authors.initials: J
authors.lastname: Baggen
authors.affiliation: Department of Molecular Cell Biology, VU University Medical Center, van der Boechorstraat 7, 1081BT Amsterdam, The Netherlands.
authors.forename: Ruud
authors.initials: R
authors.lastname: Fontijn
authors.affiliation: Department of Molecular Cell Biology, VU University Medical Center, van der Boechorstraat 7, 1081BT Amsterdam, The Netherlands.
authors.forename: Tineke
authors.initials: T
authors.lastname: van der Pouw Kraan
authors.affiliation: Department of Diabetes Center Internal medicine, VU University Medical Center, van der Boechorstraat 7, 1081BT Amsterdam, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Serné
authors.affiliation: Department of Physiology, VU University Medical Center, van der Boechorstraat 7, 1081BT Amsterdam, The Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: Koolwijk
authors.affiliation: Department of Diabetes Center Internal medicine, VU University Medical Center, van der Boechorstraat 7, 1081BT Amsterdam, The Netherlands.
authors.forename: Michaela
authors.initials: M
authors.lastname: Diamant
authors.affiliation: Department of Molecular Cell Biology, VU University Medical Center, van der Boechorstraat 7, 1081BT Amsterdam, The Netherlands. Electronic address: aj.horrevoets@vumc.nl.
authors.forename: Anton J G
authors.initials: AJ
authors.lastname: Horrevoets
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D016022:Case-Control Studies; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000503:physiopathology; D008875:Middle Aged; D018919:Neovascularization, Physiologic / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D019308:Palmitic Acid / Q000378:metabolism*; D000077185:Resveratrol; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013267:Stilbenes; D019308:Palmitic Acid; D000077185:Resveratrol
keywords: Chloromethyl-dichlorofluorescein-diacetate (PubChem CID: 90722914); Diabetes mellitus; Dimethyl sulfoxide (PubChem CID: 679); EDTA (PubChem CID: 6049); Endothelial progenitor cells; Fatty acid; Glucose (PubChem CID: 5282499); Mannitol (PubChem CID: 6251); N-Acetyl-l-cysteine (PubChem CID: 12035); Oxidative stress; Palmitic acid (PubChem CID: 985); Resveratrol (PubChem CID: 445154); SRT1720 (PubChem CID: 25232708); Sodium Dodecyl Sulfate (PubChem CID: 3423265)