Nitro-oleic acid inhibits vascular endothelial inflammatory responses and the endothelial-mesenchymal transition

• Published in: Biochimica et biophysica acta Vol. 1860; no. 11; pp. 2428 - 2437
• Main Authors: Ambrozova, Gabriela, Fidlerova, Tana, Verescakova, Hana, Koudelka, Adolf, Rudolph, Tanja K., Woodcock, Steven R., Freeman, Bruce A., Kubala, Lukas, Pekarova, Michaela
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.11.2016
• Subjects: acids; adhesion; Animals; cardiovascular diseases; cytokines; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelial-mesenchymal transition; endothelium; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; enzyme-linked immunosorbent assay; Epithelial-Mesenchymal Transition; gene expression regulation; homeostasis; Humans; immune response; inflammation; Inflammation - metabolism; Macrophages; Macrophages - drug effects; Macrophages - metabolism; MAP Kinase Signaling System; Mice; mitogen-activated protein kinase; monocytes; NF-kappa B - metabolism; Nitro-fatty acids; Nitro-oleic acid; Oleic Acids - pharmacology; phenotype; pleiotropy; Smad Proteins - metabolism; STAT Transcription Factors - metabolism; Transforming Growth Factor beta - pharmacology; Vascular inflammation; Western blotting; eNOS; Nitro-fatty acids; RANTES; Endothelial-mesenchymal transition; ICAM-1; Nitro-oleic acid; Macrophages; LPS; FSP1; α-SMA; DMEM; NF-κB; IFN-γ; GM-CSF; FBS; iNOS; TGF-β; Vascular inflammation; EndMT; EC; IL-1β; MAPK; IL-6; OA-NO2; PPARγ; Endothelial cells; STAT; TNF-α; NO2-FA; MCP-5
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2016.07.010

Inflammatory-mediated pathological processes in the endothelium arise as a consequence of the dysregulation of vascular homeostasis. Of particular importance are mediators produced by stimulated monocytes/macrophages inducing activation of endothelial cells (ECs). This is manifested by excessive soluble pro-inflammatory mediator production and cell surface adhesion molecule expression. Nitro-fatty acids are endogenous products of metabolic and inflammatory reactions that display immuno-regulatory potential and may represent a novel therapeutic strategy to treat inflammatory diseases. The purpose of our study was to characterize the effects of nitro-oleic acid (OA-NO2) on inflammatory responses and the endothelial-mesenchymal transition (EndMT) in ECs that is a consequence of the altered healing phase of the immune response. The effect of OA-NO2 on inflammatory responses and EndMT was determined in murine macrophages and murine and human ECs using Western blotting, ELISA, immunostaining, and functional assays. OA-NO2 limited the activation of macrophages and ECs by reducing pro-inflammatory cytokine production and adhesion molecule expression through its modulation of STAT, MAPK and NF-κB-regulated signaling. OA-NO2 also decreased transforming growth factor-β-stimulated EndMT and pro-fibrotic phenotype of ECs. These effects are related to the downregulation of Smad2/3. The study shows the pleiotropic effect of OA-NO2 on regulating EC-macrophage interactions during the immune response and suggests a role for OA-NO2 in the regulation of vascular endothelial immune and fibrotic responses arising during chronic inflammation. These findings propose the OA-NO2 may be useful as a novel therapeutic agent for treatment of cardiovascular disorders associated with dysregulation of the endothelial immune response. [Display omitted] •Nitro-oleic acid regulates cooperation of macrophages and endothelial cells in inflammation.•Nitro-oleic acid attenuates the inflammatory response of endothelial cells.•Nitro-oleic acid affects STAT, MAPK, and NF-κB signaling in activated endothelial cells.•Nitro-oleic acid downregulates TGF-β-induced EndMT in endothelial cells.•Smad2/3 activation is suppressed by nitro-oleic acid in TGF-β treated endothelial cells.