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Thromb Haemost 2007; 98(06): 1309-1315
DOI: 10.1160/TH07-05-0346
Platelets and Blood Cells
Schattauer GmbH

Alternative splicing of platelet cyclooxygenase-2 mRNA in patients after coronary artery bypass grafting

Petra Censarek
1   Institut fr Pharmakologie und Klinische Pharmakologie Universittsklinikum Duesseldorf, Germany
,
Gerhard Steger
2   Institut für Physikalische Biologie, Heinrich-Heine-Universität Duesseldorf, Germany
,
Carla Paolini
1   Institut fr Pharmakologie und Klinische Pharmakologie Universittsklinikum Duesseldorf, Germany
,
Thomas Hohlfeld
1   Institut fr Pharmakologie und Klinische Pharmakologie Universittsklinikum Duesseldorf, Germany
,
Tilo Grosser
3   Institute for Translational Medicine and Therapeutics and Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
,
Norbert Zimmermann
4   Bundesinstitut für Arzneimittel und Medizinprodukte, Bonn, Germany
,
Diana Fleckenstein
5   Institut für Pharmakologie, Universität Duisburg-Essen, Universitätsklinikum Essen, Germany
,
Karsten Schrör
1   Institut fr Pharmakologie und Klinische Pharmakologie Universittsklinikum Duesseldorf, Germany
,
Artur-Aron Weber
5   Institut für Pharmakologie, Universität Duisburg-Essen, Universitätsklinikum Essen, Germany
› Author Affiliations
Further Information

Publication History

Received 14 May 2007

Accepted after resubmission 02 November 2007

Publication Date:
30 November 2017 (online)

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Summary

Recently, we cloned from platelet mRNA a novel cyclooxygenase (COX)-2 splice variant, designated COX-2a, which is characterized by a partial deletion of exon 5. Preliminary studies of mRNA distribution of COX-2 isoforms in platelets from coronary artery bypass grafting (CABG) patients showed a variable increase in COX-2a mRNA expression after cardiac surgery. Thus, we assessed whether this variant may play a functional role in these patients. We report a marked (about 20346-fold) increase in the expression of COX-2a mRNA after CABG. Evidence is presented that ribosomal frame-shifting may correct the coding sequence resulting in the expression of a full-length COX-2a pro-tein. In addition, a reading frame-corrected COX-2a mutant (COX-2aΔG) was generated by site-directed mutagenesis and expressed in COS-7 cells using an adenoviral expression system. However, COX-2a protein was not active in terms of prostaglandin formation. Thus, alternative mRNA splicing might represent an intriguing posttranscriptional mechanism to oppose a transcriptional activation of the COX-2 gene. Evolutionary, this mechanism may prevent COX-2-dependent thromboxane synthesis in the platelet, which would potentiate the likelihood of thrombosis; pharmacologically, this mechanism would prevent an aspirin-insensitive pathway of thromboxane formation.

Keywords

Platelet COX-2 - COX-2a - aspirin - thromboxane - CABG - qPCR
 

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