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1 Cardiovascular Center, University of Michigan, Ann Arbor, Michigan, United States
2 Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, Georgia, United States
3 Atherogenics Inc., Alpharetta, Georgia, United States
4 Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
5 Cardiovascular Center, University of Michigan, 1150 W. Medical Center Drive, Ann Arbor, Michigan, 48109, United States
* To whom correspondence should be addressed. E-mail: tcui{at}umich.edu.
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, p27kip1. Furthermore, LNO2 triggered Nrf2 nuclear translocation and activation of the antioxidant responsive element (ARE)-driven transcriptional activity via impairing 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 p27kip1 and growth inhibition of VSMCs. In contrast, knock down of Nrf2 using an Nrf2 siRNA approach reversed the LNO2-induced upregulation of p27kip1 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.
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