Counter-regulation by atorvastatin of gene modulations induced by L-NAME hypertension is associated with vascular protection.
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.
Nadaud
Sophie
S
UPMC Univ Paris 06, UMR_S 525, Paris, France.
Dupuis
Morgan
M
Brocheriou
Isabelle
I
Haloui
Mounsif
M
Louedec
Liliane
L
Capron
Frédérique
F
Michel
Jean-Baptiste
JB
Soubrier
Florent
F
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
D006538:Heptanoic Acids; D011758:Pyrroles; D000069059:Atorvastatin; D019331:NG-Nitroarginine Methyl Ester