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20‐Hydroxyeicosatetraenoic acid inhibits ATP‐induced COX‐2 expression via peroxisome proliferator activator receptor‐α in vascular smooth muscle cells
Author(s) -
Liang ChanJung,
Tseng ChingPing,
Yang ChuenMao,
Ma YunnHwa
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2011.01263.x
Subject(s) - activator (genetics) , peroxisome proliferator activated receptor , vascular smooth muscle , transfection , response element , luciferase , receptor , biology , hydroxyeicosatetraenoic acid , small interfering rna , transcription factor , microbiology and biotechnology , chemistry , cell culture , endocrinology , gene expression , biochemistry , arachidonic acid , promoter , enzyme , genetics , smooth muscle , gene
BACKGROUND AND PURPOSE 20‐Hydroxyeicosatetraenoic acid (20‐HETE), formed from arachidonate by cytochrome P450, regulates vascular smooth muscle cell (VSMC) function. Because 20‐HETE may activate peroxisome proliferator activator receptors (PPARs) and may participate in inflammatory responses, we asked whether 20‐HETE may inhibit cyclooxygenase 2 (COX‐2) expression by activating PPARs in VSMC. EXPERIMENTAL APPROACH Quiescent neonatal VSMC (R22D cell line), were incubated with 20‐HETE, synthetic ligands of PPARs, or inhibitors of the extracellular signal regulated kinase (ERK1/2), c‐jun N‐terminal kinase and the transcription factor activated protein‐1 before adding ATPγS. mRNA and protein expression of COX‐2 and the promoter luciferase activity of COX‐2 and PPAR response element were determined. KEY RESULTS Pretreatment with 20‐HETE (5–10 µM) significantly inhibited ATPγS‐induced COX‐2 mRNA and protein expression in VSMC. The inhibitory effect of 20‐HETE on COX‐2 expression was mimicked by WY14643, a PPARα ligand and inhibited by MK886, a PPARα inhibitor or by transfection of shRNA for PPARα. Both 20‐HETE and WY14643 significantly increased the PPAR‐response element luciferase activity. Furthermore, ATPγS‐induced activation of the COX‐2 promoter containing the activated protein‐1 site was also inhibited by pretreatment with 20‐HETE, which was reversed by MK886 or by transfection with shRNA for PPARα. CONCLUSIONS AND IMPLICATIONS The PPARα may mediate the inhibitory effects of 20‐HETE on COX‐2 expression through a negative cross‐talk between PPARα and the COX‐2 promoter.