PT  - JOURNAL ARTICLE
AU  - Emilia Kansanen
AU  - Suvi M Kuosmanen
AU  - Anna-Kaisa Ruotsalainen
AU  - Heidi Hynynen
AU  - Anna-Liisa Levonen
TI  - Nitro-oleic acid regulates endothelin signaling in human endothelial cells
AID  - 10.1124/mol.117.109751
DP  - 2017 Jan 01
TA  - Molecular Pharmacology
PG  - mol.117.109751
4099  - http://molpharm.aspetjournals.org/content/early/2017/08/04/mol.117.109751.short
4100  - http://molpharm.aspetjournals.org/content/early/2017/08/04/mol.117.109751.full
AB  - Nitro-fatty acids are reactive signaling mediators that are formed when unsaturated fatty acids react with nitric oxide or nitric oxide-derived species. Nitro-fatty acids can modify specific signaling pathways via post-translational modifications of cysteine residues in key regulatory proteins. One of the signaling cascades activated by nitro-fatty acids is the Keap1-Nrf2 pathway. We have previously studied the effects of nitro-oleic acid (OA-NO2) on the human endothelial cell transcriptome. We observed that endothelin receptor B (ET-B, EDNRB), the receptor mediating the vasodilatory effects of endothelin-1 (ET-1) is induced by OA-NO2. Inasmuch as ET-1 is one of the key regulators of vascular tone, we chose to examine in more detail the effect of OA-NO2 on endothelin signaling in human endothelial cells. Nrf2 was found to regulate the OA-NO2 induced transcription of ET-B in human and mouse endothelial cells. Furthermore, ChIP analysis revealed that OA-NO2 increased binding of Nrf2 to an Antioxidant Response Element in the enhancer region of EDNRB gene. In addition, we show that both OA-NO2 and Nrf2 overexpression substantially decreased, and Nrf2 silencing increased the ET-1 concentration in the culture media of endothelial cells. The change in the extracellular ET-1 concentration was dependent on ET-B receptor expression. These data suggest that OA-NO2 modulates endothelin signaling by increasing Nrf2-dependent expression of the ET-B receptor in endothelial cells, which in turn mediates the decrease in extracellular ET-1 concentration. Based on these results, we propose that OA-NO2 and Nrf2 may alleviate vasoconstrictive effects of ET-1 by removing it from the circulation.