title: Regulation of vascular endothelial genes by dietary flavonoids: structure-expression relationship studies and the role of the transcription factor KLF-2.
abstract: Physiological concentrations (1 μM) of 15 flavonoids were evaluated in human umbilical vein endothelial cells in the presence of hydrogen peroxide (H₂O₂) for their ability to affect endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1) expression in order to establish the structural basis of their bioactivity. Flavonoid effects on eNOS transcription factor Krüpple like factor-2 (KLF-2) expression were also evaluated. All studied flavonoids appeared to be effective compounds for counteracting the oxidative stress-induced effects on vascular gene expression, indicating that flavonoids are an excellent source of functional endothelial regulator products. Notably, the more effective flavonoids for KLF-2 up-regulation resulted in the highest values for eNOS expression, showing that the increment of eNOS expression would take place through KLF-2 induction. Structure-activity relationship studies showed that the combinations of substructures on flavonoid skeleton that regulate eNOS expression are made up of the following elements: glycosylation and hydroxylation of C-ring, double bond C2=C3 at C-ring, methoxylation and hydroxylation of B-ring, ketone group in C4 at C-ring and glycosylation in C7 of A-ring, while flavonoid features involved in the reduction of vasoconstrictor ET-1 expression are as follows: double bond C2=C3 at C-ring glycosylation in C7 of A-ring and ketone group in C4 of C-ring.
authors.affiliation: Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili, Tarragona, 43007 Spain.
authors.forename: Leyre
authors.initials: L
authors.lastname: Martínez-Fernández
authors.affiliation: Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili, Tarragona, 43007 Spain.
authors.forename: Zara
authors.initials: Z
authors.lastname: Pons
authors.affiliation: Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili, Tarragona, 43007 Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Margalef
authors.affiliation: Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili, Tarragona, 43007 Spain. Electronic address: anna.arola@urv.cat.
authors.forename: Anna
authors.initials: A
authors.lastname: Arola-Arnal
authors.affiliation: Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili, Tarragona, 43007 Spain; Centre Tecnològic de Nutrició i Salut (CTNS), TECNIO, CEICS, Avinguda Universitat, 1, 43204 Reus, Catalonia, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Muguerza
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000378:metabolism*; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004032:Diet; D019332:Endothelin-1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D005419:Flavonoids / Q000737:chemistry / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006031:Glycosylation; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D006900:Hydroxylation; D051741:Kruppel-Like Transcription Factors / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015394:Molecular Structure; D052250:Nitric Oxide Synthase Type III / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016877:Oxidants / Q000037:antagonists & inhibitors / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D019332:Endothelin-1; D005419:Flavonoids; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D016877:Oxidants; D006861:Hydrogen Peroxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III
keywords: ET-1; Endothelial function; Flavonoids; KLF-2; Structure–activity relationship studies; eNOS