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Cardiovascular Research Advance Access [Accepted Manuscript] published online on February 20, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp069
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Functional Coupling Expression of COX-2 and cPLA2 Induced by ATP in Rat Vascular Smooth Muscle Cells: Role of ERK1/2, p38 MAPK, and NF-{kappa}B

Chih-Chung Lina,{dagger}, Wei-Ning Linsb,{dagger}, Wei-Jung Wangb, Chi-Chin Sunc, Wei-Hsuan Tungb, Hui-Hsin Wangb and Chuen-Mao Yangb,*

a Department of Anesthetics;
b Department of Physiology and Pharmacology, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan
c Department of Ophthalmology, Chang Gung Memorial Hospital, Keelung, Taiwan

* Correspondence and requests for reprints should be addressed to: Chuen-Mao Yang, Ph.D. Department of Pharmacology Chang Gung University 259 Wen-Hwa 1st Road, Kwei-San, Tao-Yuan, Taiwan TEL (03) 2118800 EXT 5123 FAX (03) 2118365 E-Mail: chuenmao{at}mail.cgu.edu.tw

AIMS: Vascular smooth muscle cells (VSMCs) that function as synthetic units play important roles in inflammatory diseases such as atherosclerosis and angiogenesis. As extracellular nucleotides such as ATP have been shown to act via activation of P2 purinoceptors implicated in various inflammatory diseases, we hypothesized that extracellular nucleotides contribute to vascular diseases via upregulated expression of inflammatory proteins, such as cyclooxygenase (COX-2) and cytosolic phospholipase A2 (cPLA2) in VSMCs.

METHODS AND RESULTS: Western blotting, promoter assay, RT-PCR, and PGE2 immunoassay revealed that ATP{gamma}S induced expression of COX-2 and prostaglandin (PGE2) synthesis through the activation of p42/p44 MAPK (mitogen-activated protein kinase), p38 MAPK, and nuclear factor-{kappa}B (NF-{kappa}B). These responses were attenuated by inhibitors of MAPK/ERK kinase (MEK1/2; U0126), p38 MAPK (SB202190), and NF-{kappa}B (helenalin), or by tranfection with dominant negative mutants of p42, p38, I{kappa}B kinase (IKK){alpha}, and IKKβ. Furthermore, the ATP{gamma}S-stimulated translocation of NF-{kappa}B into the nucleus and degradation of I{kappa}B{alpha} was blocked by U0126 and helenalin. In addition, the ATP{gamma}S-stimulated cPLA2 expression was inhibited by U0126, SB202190, helenalin, celecoxib (a selective COX-2 inhibitor), and PGE2 receptor antagonists (AH6809, GW627368X, and SC-19220). However, the inhibitory effect of celecoxib on cPLA2 expression was reversed by addition of exogenous PGE2.

CONCLUSION: Our results suggest that in VSMCs, activation of p42/p44 MAPK, p38 MAPK, and NF-{kappa}B is essential for ATP{gamma}S-induced COX-2 expression and PGE2 synthesis. Newly synthesized PGE2 was observed to act as an autocrine signal contributing to cPLA2 expression, which may be implicated in inflammatory responses. Collectively, our findings provide insights into the correlation between COX-2 and cPLA2 expression in ATP{gamma}S-stimulated VSMCs with similar molecular mechanisms and functional coupling to amplify the occurrence of vessel diseases-related vascular inflammation.

Time for primary review: 14 Days

{dagger} These authors have equal contribution in this work.


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