Nitro-linoleic acid inhibits vascular smooth muscle cell proliferation via the Keap1/Nrf2 signaling pathway
Open accessAbstract
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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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].”
From Olives and olive oil are sources of electrophilic fatty acid nitroalkenes (2014) · cites this paper as [46]
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].”
From Olives and olive oil are sources of electrophilic fatty acid nitroalkenes (2014) · cites this paper as [46]
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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
- Publisher
- American Physiological Society
- Published
- 2007-07
- Volume
- 293
- Issue
- 1
- Pages
- H770-H776
- ISSN
- 0363-6135 (ISSN-L)
- 1522-1539
- PMC
- PMC2170893
- 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
- green
- www.ncbi.nlm.nih.gov
- 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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