title: Counter-regulation by atorvastatin of gene modulations induced by L-NAME hypertension is associated with vascular protection.
abstract: Statins, 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, protect against deleterious effects of chronic nitric oxide inhibition. We aimed at determining the genes and pathways involved in the protective effect of statin treatment during hypertension. Chronic inhibition of nitric oxide synthesis by Nomega-nitro-L-arginine methyl ester (L-NAME) induced accelerated hypertension which was slightly reduced by cotreatment with atorvastatin (100 mg/kg/day). Gene expression profile of aortic media was strongly modified by atorvastatin cotreatment which prevented modulation of many genes regulated by L-NAME administration (described in Dupuis, M., Soubrier, F., Brocheriou, I., Raoux, S., Haloui, M., Louedec, L., Michel, J.B., Nadaud, S., 2004. Profiling of aortic smooth muscle cell gene expression in response to chronic inhibition of nitric oxide synthase in rats. Circulation 110, 867-873). The functional classification of these genes highlighted several major biological pathways modulated in aortic media by atorvastatin: effectors involved in smooth muscle tone; extracellular matrix; intracellular mediators of cell proliferation. Moreover, atorvastatin partially prevented arterial wall thickening, TGF-beta pathway activation, MCP-1 induction and smooth muscle cell proliferation induced by L-NAME treatment although blood pressure was only slightly reduced, suggesting mechanisms independent of blood pressure levels. The induction of PPARalpha mRNA expression by atorvastatin in L-NAME treated rats also suggests that this pathway could participate in the protective effect. In conclusion, our data show that atorvastatin specifically antagonizes a set of genes modulated by L-NAME-induced accelerated hypertension.
authors: UPMC Univ Paris 06, UMR_S 525, Paris, France.
authors: Sophie
authors: S
authors: Nadaud
authors: Morgan
authors: M
authors: Dupuis
authors: Isabelle
authors: I
authors: Brocheriou
authors: Mounsif
authors: M
authors: Haloui
authors: Liliane
authors: L
authors: Louedec
authors: Frédérique
authors: F
authors: Capron
authors: Jean-Baptiste
authors: JB
authors: Michel
authors: Florent
authors: F
authors: Soubrier
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D000069059:Atorvastatin; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D005786:Gene Expression Regulation; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D006973:Hypertension / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000633:toxicity*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D006538:Heptanoic Acids; D011758:Pyrroles; D000069059:Atorvastatin; D019331:NG-Nitroarginine Methyl Ester