title: Fenofibrate improves vascular endothelial function by reducing oxidative stress while increasing endothelial nitric oxide synthase in healthy normolipidemic older adults.
abstract: Vascular endothelial dysfunction develops with aging, as indicated by impaired endothelium-dependent dilation, and is related to increased cardiovascular disease risk. We hypothesized that short-term treatment with fenofibrate, a lipid-lowering agent with potential pleiotropic effects, would improve endothelium-dependent dilation in middle-aged and older normolipidemic adults by reducing oxidative stress. Brachial artery flow-mediated dilation, a measure of endothelium-dependent dilation, was assessed in 22 healthy adults aged 50 to 77 years before and after 7 days of fenofibrate (145 mg/d; n=12) or placebo (n=10). Brachial flow-mediated dilation was unchanged with placebo, but improved after 2 and 7 days of fenofibrate (5.1 ± 0.7 versus 2 days: 6.0 ± 0.7 and 7 days: 6.4 ± 0.6%δ; both P<0.005). The improvements in flow-mediated dilation after 7 days remained significant (P<0.05) after accounting for modest changes in plasma total and low-density lipoprotein cholesterol. Endothelium-independent dilation was not affected by fenofibrate or placebo (P>0.05). Intravenous infusion of the antioxidant vitamin C improved brachial flow-mediated dilation at baseline in both groups and during placebo treatment (P<0.05), but not after 2 and 7 days of fenofibrate (P>0.05). Fenofibrate treatment also reduced plasma-oxidized low-density lipoprotein, a systemic marker of oxidative stress, compared with placebo (P<0.05). In vascular endothelial cells sampled from peripheral veins of the subjects, endothelial nitric oxide synthase protein expression was unchanged with placebo and after 2 days of fenofibrate, but was increased after 7 days of fenofibrate (0.54 ± 0.03 versus 2 days: 0.52 ± 0.04 and 7 days: 0.76 ± 0.11 intensity/human umbilical vein endothelial cell control; P<0.05, 7 days). Short-term treatment with fenofibrate improves vascular endothelial function in healthy normolipidemic middle-aged and older adults by reducing oxidative stress and induces an increase in endothelial nitric oxide synthase.
authors.affiliation: Department of Integrative Physiology, University of Colorado, Boulder, CO, USA. Ashley.Walker@utah.edu
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Walker
authors.forename: Rachelle E
authors.initials: RE
authors.lastname: Kaplon
authors.forename: Sara Marian S
authors.initials: SM
authors.lastname: Lucking
authors.forename: Molly J
authors.initials: MJ
authors.lastname: Russell-Nowlan
authors.forename: Robert H
authors.initials: RH
authors.lastname: Eckel
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Seals
mesh_terms: D000368:Aged; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D001916:Brachial Artery / Q000187:drug effects / Q000502:physiology; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D011345:Fenofibrate / Q000494:pharmacology*; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D016896:Treatment Outcome; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D000975:Antioxidants; D000960:Hypolipidemic Agents; D052250:Nitric Oxide Synthase Type III; D001205:Ascorbic Acid; D011345:Fenofibrate