title: Atorvastatin restores endothelial function in offspring of protein-restricted rats in a cholesterol-independent manner.
abstract: Maternal protein restriction in rats leads to endothelial dysfunction and decreased NO bioavailability in the offspring. Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) are recognized to have pleiotropic actions including increasing NO bioavailability and reducing inflammation and oxidative damage. This study assessed statin treatment on vascular function in a model of endothelial dysfunction, which is independent of dyslipidemia. Wistar rats were fed a control (18% casein) or protein-restricted (9% casein) diet throughout pregnancy. At weaning, a subset of the protein-restricted group was given atorvastatin (10 mg/kg per day) in the drinking water. At 145 days of age, offspring were euthanized by CO(2) inhalation. Plasma samples were collected for markers of inflammation, vascular reactivity of the thoracic aorta, and small mesenteric arteries were assessed on the wire myograph, and tissues were snap frozen for molecular biology analysis. Thoracic aorta endothelial-dependent vasodilatation was attenuated in the male offspring from both protein-restricted groups compared with controls (P<0.05) but was similar in females (P value not significant). Endothelial-dependent dilatation of mesenteric arteries was attenuated in male and female protein-restricted offspring (P<0.05) and was corrected by atorvastatin. Maternal protein restriction increased plasma inflammatory markers granulocyte chemotactic protein, lipocalin-2, and beta(2)-microglobulin in male and C-reactive protein in female offspring (P<0.05). Atorvastatin had no effect on inflammatory markers in the males but restored C-reactive protein to control levels in the females (P<0.05). Aortic and mesenteric artery mRNA levels of endothelial NO synthase, superoxide dismutase 1, and tumor necrosis factor-alpha were unchanged. These data suggest that atorvastatin can restore endothelial function in this model, but its effects are gender specific and dependent on the vascular bed.
authors.affiliation: Vascular Biology Group, Institute of Developmental Sciences (887), University of Southampton, School of Medicine, Southampton General Hospital, Tremona Rd, Southampton S016 6YD, United Kingdom. c.torrens@southampton.ac.uk.
authors.forename: Christopher
authors.initials: C
authors.lastname: Torrens
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kelsall
authors.forename: Laura A
authors.initials: LA
authors.lastname: Hopkins
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Anthony
authors.forename: Nick P
authors.initials: NP
authors.lastname: Curzen
authors.forename: Mark A
authors.initials: MA
authors.lastname: Hanson
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006538:Heptanoic Acids / Q000097:blood / Q000494:pharmacology*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000188:drug therapy / Q000503:physiopathology; D011502:Protein-Energy Malnutrition / Q000150:complications / Q000503:physiopathology*; D011758:Pyrroles / Q000097:blood / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014657:Vasculitis / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D015430:Weight Gain
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D012333:RNA, Messenger; D002784:Cholesterol; D000069059:Atorvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat