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  Arachidonic Acid Metabolite 19(S)-HETE Induces Vasorelaxation and Platelet Inhibition by Activating Prostacyclin (IP) Receptor

Tunaru, S., Chennupati, R., Nuesing, R. M., & Offermanns, S. (2016). Arachidonic Acid Metabolite 19(S)-HETE Induces Vasorelaxation and Platelet Inhibition by Activating Prostacyclin (IP) Receptor. PLOS ONE, 11(9): e0163633. doi:10.1371/journal.pone.0163633.

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 Creators:
Tunaru, Sorin1, Author              
Chennupati, Ramesh1, Author              
Nuesing, Rolf M., Author
Offermanns, Stefan1, Author              
Affiliations:
1Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591696              

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Free keywords: PROSTANOID RECEPTORS; MOUSE ARTERIES; CYTOCHROME-P450; CYCLOOXYGENASE; INDOMETHACIN; FIBROSIS; RELEASE; BRAINScience & Technology - Other Topics;
 Abstract: 19(S)-hydroxy-eicosatetraenoic acid (19(S)-HETE) belongs to a family of arachidonic acid metabolites produced by cytochrome P450 enzymes, which play critical roles in the regulation of cardiovascular, renal and pulmonary functions. Although it has been known for a long time that 19(S)-HETE has vascular effects, its mechanism of action has remained unclear. In this study we show that 19(S)-HETE induces cAMP accumulation in the human megakaryoblastic leukemia cell line MEG-01. This effect was concentration-dependent with an EC50 of 520 nM, insensitive to pharmacological inhibition of COX-1/2 and required the expression of the G-protein G(s). Systematic siRNA-mediated knock-down of each G-protein coupled receptor (GPCR) expressed in MEG-01 followed by functional analysis identified the prostacyclin receptor (IP) as the mediator of the effects of 19(S)-HETE, and the heterologously expressed IP receptor was also activated by 19(S)-HETE in a concentration- dependent manner with an EC50 of 567 nM. Pretreatment of isolated murine platelets with 19(S)-HETE blocked thrombin-induced platelets aggregation, an effect not seen in platelets from mice lacking the IP receptor. Furthermore, 19(S)-HETE was able to relax mouse mesenteric artery-and thoracic aorta-derived vessel segments. While pharmacological inhibition of COX-1/2 enzymes had no effect on the vasodilatory activity of 19(S)HETE these effects were not observed in vessels from mice lacking the IP receptor. These results identify a novel mechanism of action for the CYP450-dependent arachidonic acid metabolite 19(S)-HETE and point to the existence of a broader spectrum of naturally occurring prostanoid receptor agonists.

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Language(s): eng - English
 Dates: 2016
 Publication Status: Published online
 Pages: 16
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
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Title: PLOS ONE
Source Genre: Journal
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Publ. Info: 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA : PUBLIC LIBRARY SCIENCE
Pages: - Volume / Issue: 11 (9) Sequence Number: e0163633 Start / End Page: - Identifier: ISSN: 1932-6203