Cited by 144Genomics, phytochemicals, and oxidative stressNitric Oxide and Endothelin EffectsEicosanoids and Hypertension Pharmacology

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

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Villacorta, Luis, Zhang, Jifeng, Garcia-Barrio, Minerva T., Chen, Xi-lin, Freeman, Bruce A., Chen, Yuqing E., Cui, Taixing·2007·American Journal of Physiology-Heart and Circulatory Physiology

Abstract

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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Crossref · 10.1152/ajpheart.00261.2007

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  • After fatty acid nitration and conferral of electrophilic reactivity, NO2-FA potently modulate these same pathways at nM concentrations.

    “In contrast, after fatty acid nitration and conferral of electrophilic reactivity, NO2-FA potently modulate these same pathways at nM concentrations [46], [54].”
  • NO2-FA activate Nrf2-regulated anti-inflammatory gene expression and heat shock factor-regulated heat shock protein expression.

    “Additionally, NO2-FA activate Nrf2-regulated anti-inflammatory gene expression and heat shock factor-regulated heat shock protein expression [17], [46], [55].”

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Authors
Villacorta, L., Zhang, J., Garcia-Barrio, M. T., Chen, X.-L., Freeman, B. A., Chen, Y. E., & Cui, T.
Affiliations
University of Michigan (US)
Venue
American Journal of Physiology-Heart and Circulatory Physiology
Published
2007-07
Volume
293
Issue
1
Pages
H770-H776
ISSN
  • 0363-6135 (ISSN-L)
  • 1522-1539
OpenAlex
W2004517091
Cited by
144
References
50
Citations by year
2026: 2 · 2025: 7 · 2024: 4 · 2023: 3 · 2022: 3 · 2021: 2 · 2020: 8 · 2019: 6 · 2018: 10 · 2017: 8 · 2016: 9 · 2015: 6 · 2014: 8 · 2013: 10 · 2012: 10
FWCI
5.43
Type
journal article
Language
en
Open access
Locations
  • American Journal of Physiology-Heart and Circulatory Physiology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Heart, Lung, and Blood Institute (HL 64937, R01HL064937, HL 58115, HL 075397, HL-068878, R37HL058115, R01HL058115, R01HL068878, R01HL075397)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
Keywords
nitroalkenes, vascular smooth muscle cell proliferation, Nrf2/Keap1 pathway, Nrf2 nuclear translocation, p27, cell cycle arrest, G1/S phase, antioxidant response element, vascular biology
MeSH terms
Kelch-Like ECH-Associated Protein 1, Animals, Cells, Cultured, Dose-Response Relationship, Drug, Linoleic Acids, Male, Muscle, Smooth, Vascular, Nitro Compounds, Proteins, Signal Transduction, Rats, Sprague-Dawley, Myocytes, Smooth Muscle, Intracellular Signaling Peptides and Proteins, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p27, NF-E2-Related Factor 2, Rats

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