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This Article Full Text Full Text (PDF) All Versions of this Article: 293/1/H770    most recent 00261.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Villacorta, L. Articles by Cui, T. Search for Related Content PubMed PubMed Citation Articles by Villacorta, L. Articles by Cui, T.

Nitro-linoleic acid inhibits vascular smooth muscle cell proliferation via the Keap1/Nrf2 signaling pathway

¹Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan; ²Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta; ³Atherogenics Inc., Alpharetta, Georgia; and ⁴Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Submitted 2 March 2007 ; accepted in final form 27 April 2007

Nitroalkenes, the nitration products of unsaturated fatty acids formed via NO-dependent oxidative reactions, have been demonstrated to exert strong biological actions in endothelial cells and monocytes/macrophages; however, little is known about their effects on vascular smooth muscle cells (VSMCs). The present study examined the role of nitro-linoleic acid (LNO₂) in the regulation of VSMC proliferation. We observed that LNO₂ inhibited VSMC proliferation in a dose-dependent manner. In addition, LNO₂ induced growth arrest of VSMCs in the G₁/S phase of the cell cycle with an upregulation of the cyclin-dependent kinase inhibitor p27^kip1. Furthermore, LNO₂ triggered nuclear factor-erythroid 2-related factor 2 (Nrf2) nuclear translocation and activation of the antioxidant-responsive element-driven transcriptional activity via impairing Kelch-like ECH-associating protein 1 (Keap1)-mediated negative control of Nrf2 activity in VSMCs. LNO₂ upregulated the expression of Nrf2 protein levels, but not mRNA levels, in VSMCs. A forced activation of Nrf2 led to an upregulation of p27^kip1 and growth inhibition of VSMCs. In contrast, knock down of Nrf2 using an Nrf2 siRNA approach reversed the LNO₂-induced upregulation of p27^kip1 and inhibition of cellular proliferation in VSMCs. These studies provide the first evidence that nitroalkene LNO₂ inhibits VSMC proliferation through activation of the Keap1/Nrf2 signaling pathway, suggesting an important role of nitroalkenes in vascular biology.

nitroalkenes; nuclear factor-erythroid 2-related factor 2; Kelch-like ECH-associating protein 1