Document Detail


Nitro-linoleic acid inhibits vascular smooth muscle cell proliferation via the Keap1/Nrf2 signaling pathway.
MedLine Citation:
PMID:  17468336     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Luis Villacorta; Jifeng Zhang; Minerva T Garcia-Barrio; Xi-lin Chen; Bruce A Freeman; Yuqing E Chen; Taixing Cui
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2007-04-27
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  293     ISSN:  0363-6135     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2007 Jul 
Date Detail:
Created Date:  2007-07-12     Completed Date:  2007-09-12     Revised Date:  2014-09-18    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H770-6     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Proliferation / drug effects*
Cells, Cultured
Cyclin-Dependent Kinase Inhibitor p27 / metabolism
Dose-Response Relationship, Drug
Intracellular Signaling Peptides and Proteins
Linoleic Acids / administration & dosage*
Male
Muscle, Smooth, Vascular / cytology,  drug effects,  physiology*
Myocytes, Smooth Muscle / cytology,  drug effects,  physiology*
NF-E2-Related Factor 2 / metabolism*
Nitro Compounds / administration & dosage*
Proteins / metabolism*
Rats
Rats, Sprague-Dawley
Signal Transduction / drug effects,  physiology*
Grant Support
ID/Acronym/Agency:
HL 068878/HL/NHLBI NIH HHS; HL 075397/HL/NHLBI NIH HHS; HL 58115/HL/NHLBI NIH HHS; HL 64937/HL/NHLBI NIH HHS; R01 HL058115/HL/NHLBI NIH HHS; R01 HL058115-10/HL/NHLBI NIH HHS; R01 HL064937/HL/NHLBI NIH HHS; R01 HL064937-06/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/10-nitro-9,12-octadecadienoic acid; 0/Intracellular Signaling Peptides and Proteins; 0/KEAP1 protein, rat; 0/Linoleic Acids; 0/NF-E2-Related Factor 2; 0/Nitro Compounds; 0/Proteins; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27
Comments/Corrections

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