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Am J Physiol Heart Circ Physiol. 2007 Jul;293(1):H770-6. Epub 2007 Apr 27.

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

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Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical Center, 1150 W. Medical Center Drive, Ann Arbor, MI 48109, USA.


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 (LNO(2)) in the regulation of VSMC proliferation. We observed that LNO(2) inhibited VSMC proliferation in a dose-dependent manner. In addition, LNO(2) induced growth arrest of VSMCs in the G(1)/S phase of the cell cycle with an upregulation of the cyclin-dependent kinase inhibitor p27(kip1). Furthermore, LNO(2) 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. LNO(2) 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 LNO(2)-induced upregulation of p27(kip1) and inhibition of cellular proliferation in VSMCs. These studies provide the first evidence that nitroalkene LNO(2) inhibits VSMC proliferation through activation of the Keap1/Nrf2 signaling pathway, suggesting an important role of nitroalkenes in vascular biology.

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