title: γ-Carboxyethyl hydroxychroman, a metabolite of γ-tocopherol, preserves nitric oxide bioavailability in endothelial cells challenged with high glucose.
abstract: Endothelial dysfunction occurs when there are imbalances between factors that regulate the synthesis and degradation of nitric oxide (NO•), and has been reported in patients with hyperglycemia and insulin resistance. We reported that supplementation with γ-tocopherol (γ-T) in humans limits impairments in endothelial function otherwise induced by postprandial hyperglycemia. Given the rapid metabolism of γ-T into γ-carboxyethyl hydroxychroman (γ-CEHC), we hypothesized that the vasoprotective activities of γ-T could be attributed to its metabolite γ-CEHC. To test this, human aortic endothelial cells (HAECs) treated with 0 (vehicle control) or 3 µM γ-CEHC for 24 h prior to incubation with normal (5 mM) or high (25 mM) glucose for 48 h. High-glucose increased levels of uncoupled endothelial nitric oxide synthase (eNOS) as evidenced by reduced ( p < 0.05) eNOS dimer:monomer. High glucose also prevented insulin-stimulated increases in p-AktSer473: total Akt, p-eNOSSer1177: total eNOS, and NO•production. These adverse changes were accompanied by increased ( p < 0.05) reactive oxygen species and mRNA expression of inflammatory mediators (VCAM-1, E-selectin, IL-8). However, each deleterious response evoked by high glucose was prevented when HAECs were incubated with γ-CEHC prior to the high glucose challenge. Taken together, our data support the hypothesis that vascular protection provided by γ-T in vivo may be elicited through the bioactivity of its metabolite, γ-CEHC. Furthermore, it is possible that the antioxidant and anti-inflammatory activities of γ-CEHC may mediate this protective activity.
authors.affiliation: 1 Department of Aerospace Physiology, Fourth Military Medical University, Xi'an 710032, China.|2 Division of Endocrinology, Metabolism, and Diabetes, University of Utah, Salt Lake City, UT 84112, USA.|3 Molecular Medicine Program, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Youyou
authors.initials: Y
authors.lastname: Li
authors.affiliation: 2 Division of Endocrinology, Metabolism, and Diabetes, University of Utah, Salt Lake City, UT 84112, USA.|3 Molecular Medicine Program, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Leena P
authors.initials: LP
authors.lastname: Bharath
authors.affiliation: 4 Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Qian
authors.affiliation: 2 Division of Endocrinology, Metabolism, and Diabetes, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Ruan
authors.affiliation: 4 Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Pon Velayutham
authors.initials: PV
authors.lastname: Anandh Babu
authors.affiliation: 5 Department of Nutrition, Human Nutrition Program, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Bruno
authors.affiliation: 2 Division of Endocrinology, Metabolism, and Diabetes, University of Utah, Salt Lake City, UT 84112, USA.|3 Molecular Medicine Program, University of Utah, Salt Lake City, UT 84112, USA.|4 Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: J David
authors.initials: JD
authors.lastname: Symons
authors.affiliation: 4 Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Thunder
authors.initials: T
authors.lastname: Jalili
mesh_terms: D001682:Biological Availability; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007333:Insulin Resistance; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D002839:Chromans; D011422:Propionates; D017382:Reactive Oxygen Species; C107690:2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D005947:Glucose
keywords: endothelial cell; glucose; nitric oxide; vitamin E; γ-CEHC