title: Dietary quercetin attenuates oxidant-induced endothelial dysfunction and atherosclerosis in apolipoprotein E knockout mice fed a high-fat diet: a critical role for heme oxygenase-1.
abstract: Several lines of evidence indicate that quercetin, a polyphenol derived in the diet from fruit and vegetables, contributes to cardiovascular health. We aimed to investigate the effects of dietary quercetin on endothelial function and atherosclerosis in mice fed a high-fat diet. Wild-type C57BL/6 (WT) and apolipoprotein E gene knockout (ApoE(-/-)) mice were fed: (i) a high-fat diet (HFD) or (ii) a HFD supplemented with 0.05% w/w quercetin (HFD+Q), for 14 weeks. Compared with animals fed HFD, HFD+Q attenuated atherosclerosis in ApoE(-/-) mice. Treatment with the HFD+Q significantly improved endothelium-dependent relaxation of aortic rings isolated from WT but not ApoE(-/-) mice and attenuated hypochlorous acid-induced endothelial dysfunction in aortic rings of both WT and ApoE(-/-) mice. Mechanistic studies revealed that HFD+Q significantly improved plasma F2-isoprostanes, 24h urinary nitrite, and endothelial nitric oxide synthase activity, and increased heme oxygenase-1 (HO-1) protein expression in the aortas of both WT and ApoE(-/-) mice (P<0.05). HFD+Q also resulted in small changes in plasma cholesterol (P<0.05 in WT) and plasma triacylglycerols (P<0.05 in ApoE (-/-)mice). In a separate experiment, quercetin did not protect against hypochlorite-induced endothelial dysfunction in arteries obtained from heterozygous HO-1 gene knockout mice with low expression of HO-1 protein. Quercetin protects mice fed a HFD against oxidant-induced endothelial dysfunction and ApoE(-/-) mice against atherosclerosis. These effects are associated with improvements in nitric oxide bioavailability and are critically related to arterial induction of HO-1.
authors.affiliation: Medical School, Department of Cardiology, Drum Tower Hospital, Nanjing University, Nanjing, China; School of Medicine and Pharmacology, University of Western Australia, Perth, Australia.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shen
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Perth, Australia.
authors.forename: Natalie C
authors.initials: NC
authors.lastname: Ward
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Perth, Australia.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Hodgson
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Perth, Australia.
authors.forename: Ian B
authors.initials: IB
authors.lastname: Puddey
authors.affiliation: Centre for Vascular Research, School of Medical Sciences (Pathology) and Bosch Institute, University of Sydney, Sydney, Australia.
authors.forename: Yutang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Vascular Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, Sydney Australia.
authors.forename: Di
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Vascular Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, Sydney Australia.
authors.forename: Ghassan J
authors.initials: GJ
authors.lastname: Maghzal
authors.affiliation: Centre for Vascular Research, School of Medical Sciences (Pathology) and Bosch Institute, University of Sydney, Sydney, Australia; Vascular Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, Sydney Australia.
authors.forename: Roland
authors.initials: R
authors.lastname: Stocker
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Perth, Australia. Electronic address: Kevin.croft@uwa.edu.au.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Croft
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001011:Aorta / Q000201:enzymology; D050197:Atherosclerosis / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D059305:Diet, High-Fat / Q000009:adverse effects; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000473:pathology; D004790:Enzyme Induction; D005260:Female; D051547:Heme Oxygenase-1 / Q000502:physiology*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D011794:Quercetin / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D000975:Antioxidants; D008565:Membrane Proteins; D016877:Oxidants; D002784:Cholesterol; D011794:Quercetin; D019001:Nitric Oxide Synthase; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse
keywords: 1,1-diethyl-2-hydroxy-2-nitroso-hydrazine; ACh; ApoE(−/−); Atherosclerosis; DEANO; Endothelial function; Flavonoid; HAEC; HFD; HO-1; HOCl; NO; Oxidative stress; Polyphenol; Q; Quercetin; ROS; WT; acetylcholine; apolipoprotein E gene knockout; heme oxygenase-1; high-fat diet; human aortic endothelial cells; hypocholorous acid; nitric oxide; quercetin; reactive oxygen species; wild-type