Autocrine and paracrine transcriptional regulation of type IIA secretory phospholipase A2 gene in vascular smooth muscle cells.
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.


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-kappaB, 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 heparan-sulfate proteoglycans to show that the binding of wild-type sPLA2-IIA 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.
Jaulmes
Amandine
A
UMR Physiologie et Physiopathologie, Université Pierre et Marie Curie, Paris, France.
Janvier
Brigitte
B
Andreani
Marise
M
Raymondjean
Michel
M
D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D019898:Autocrine Communication / Q000502:physiology; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D054501:Group II Phospholipases A2; D006801:Humans; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology*; D016328:NF-kappa B / Q000378:metabolism; D019899:Paracrine Communication / Q000502:physiology; D010741:Phospholipases A / Q000235:genetics* / Q000378:metabolism*; D054467:Phospholipases A2; D011485:Protein Binding; D011509:Proteoglycans / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D054507:Receptors, Phospholipase A2; D015533:Transcriptional Activation / Q000502:physiology; D051540:Winged-Helix Transcription Factors / Q000378:metabolism
D022762:CCAAT-Enhancer-Binding Proteins; D016328:NF-kappa B; C516360:PLA2R1 protein, human; D011509:Proteoglycans; D011956:Receptors, Cell Surface; D054507:Receptors, Phospholipase A2; D051540:Winged-Helix Transcription Factors; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2