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(Circulation. 2004;110:867-873.)
© 2004 American Heart Association, Inc.

Original Articles

Profiling of Aortic Smooth Muscle Cell Gene Expression in Response to Chronic Inhibition of Nitric Oxide Synthase in Rats

Morgan Dupuis, MS; Florent Soubrier, MD, PhD; Isabelle Brocheriou, MD; Ségolène Raoux, MS; Mounsif Haloui, PhD; Liliane Louedec, MS; Jean-Baptiste Michel, MD, PhD; Sophie Nadaud, PhD

From Unit 525 INSERM, Faculté de Médecine Pitié-Salpétrière (M.D., F.S., I.B., S.R., S.N.), and Unit 460 INSERM, CHU X. Bichat (M.H., L.L., J.-B.M.), Paris, France.

Correspondence to Florent Soubrier, MD, PhD, INSERM U525, Faculté de Médecine Pitié-Salpétrière, 91 boulevard de l’Hôpital, 75013 Paris, France. E-mail florent.soubrier{at}chups.jussieu.fr

Received December 9, 2003; revision received March 30, 2004; accepted April 13, 2004.

Background— Chronic inhibition of nitric oxide (NO) synthesis by N-nitro-L-arginine methyl ester (L-NAME) induces hypertension associated with remodeling of the arterial wall. In this study, we aimed at identifying genes and pathways involved in this process in aortic smooth muscle cells from Fischer 344 rats, which exhibit an accelerated hypertension after administration of L-NAME.

Methods and Results— We studied the transcriptional profile of aortic media after 15 days (moderate hypertension) and 30 days (accelerated hypertension) of L-NAME administration (50 mg · kg^–1 · d^–1) by using rat Affymetrix Genechips, and we present a large-scale validation of the DNA chip results by real-time reverse transcription–polymerase chain reaction (RT-PCR). We observed, in aortic media, a progressive increase in the number of modulated genes during L-NAME administration, with 53 genes significantly modulated after 15 days and 147 genes after 30 days. These expression changes were confirmed at 87% by RT-PCR. We found 28 known genes regulated at both 15 and 30 days (96% confirmation by RT-PCR). The functional classification of the regulated genes highlights 3 major biological pathways modulated in aortic media during L-NAME administration: genes regulating cell proliferation, genes involved in the extracellular matrix remodeling, and genes of the NO/cGMP signaling pathway.

Conclusions— As a consequence of the genomic approach, we observed a large increase in modulation of gene expression along the evolution of the model and the progressive implication of compensatory mechanisms, making expression profile analysis more complex.

Key Words: hypertension • aorta • muscle, smooth • transcription

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