on March 31, 2005
Published online before print March 31, 2005, doi: 10.1161/01.ATV.0000164310.67356.a9
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Submitted on December 22, 2004
Accepted on March 9, 2005
Autocrine and Paracrine Transcriptional Regulation of Type IIA Secretory Phospholipase A2 Gene in Vascular Smooth Muscle Cells
Amandine Jaulmes ;
From UMR Physiologie et Physiopathologie, Université Pierre et Marie Curie, Paris, France.
* To whom correspondence should be addressed. E-mail: michel.raymondjean{at}snv.jussieu.fr.
Objective--The inflammation that occurs during the development of atherosclerosis is characterized by a massive release of sPLA2-IIA (group IIA secretory phospholipase A2) from vascular smooth muscle cells (VSMCs). We have investigated the autocrine function of sPLA2-IIA in rat aortic and human VSMCs.
Methods and Results--We found that the transcription of the endogenous sPLA2-IIA gene increased by adding a cell supernatant containing human sPLA2-IIA proteins. We show that this effect was independent of the sPLA2 activity using sPLA2-IIA proteins lacking enzyme activity. Transient transfections with various sPLA2-IIA rat promoter-luciferase constructs demonstrated that the C/EBP, NK-
B, and Ets transcription factors are involved in the increase in sPLA2-IIA gene transcription. We also found the M-type sPLA2 receptor mRNA in VSMCs, and we showed that the sPLA2-luciferase reporter gene was induced by the specific agonist of the sPLA2 receptor, aminophenylmannopyranoside (APMP), and that this induction was mediated by the same transcription factor-binding sites. Finally, we used a sPLA2-IIA mutant unable to bind heparin-sulfate proteoglycans to show that the binding of sPLA2-IIA wild-type to proteoglycans is essential for the induction of an autocrine loop.
Conclusions--We have thus identified new autocrine and paracrine pathways activating sPLA2-IIA gene expression in rat and human VSMCs.
Key words: atherosclerosis • autocrine/paracrine effects • type IIA sPLA2 • vascular smooth muscle cells
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