Project Details
Abstract
Atherosclerosis is a risk factor of morbidity and mobility, which is recognized as an
inflammatory disease. Extracellular ATP has been considered as a critical modulator of
inflammatory responses of the vessel resident cells including vascular smooth muscle cells
(VSMC). Several lines of evidence demonstrate that activation of P2Y receptors induces
breakdown of phosphoinositide, leading to activation of PKC and mobilization of intracellular
Ca2+ in VSMC. Extracellular ATP also mediates activation of cPLA2 and release of PGs
through activation of P2Y receptor. Several external stimuli have been shown to induce
activation and up-regulation of cPLA2 mediated through activation of p42/p44 MAPK, p38
MAPK, the c-jun-N-terminal kinase (JNK), PI3K/Akt, and NF-B. Up-regulation of cPLA2
has been implicated in the pathogenesis of inflammatory diseases. Induction of COX-2
expression is also mediated through MAPKs and PI3K/NF-κB pathway, respectively. The
production of eicosanoids is controlled by the availability of free arachidonic acid (AA)
released by cPLA2 which was further converted by COX-2. The elevated level of eicosanoids
has been shown to be implicated in vascular diseases. Our hypothesis of this proposal is that
up-regulation of cPLA2 and COX-2 induced by ATP may contribute to inflammatory
responses in atherosclerosis. However, the relationship of cPLA2 and COX-2 expression
induced by ATP and their signal transduction pathways in VSMC remain unknown. Therefore,
this proposal will be focus to investigate the mechanisms underlying the intracellular
signaling involved in cPLA2 and COX-2 expression induced by ATP in VSMC. In addressing
these questions, the experiments will be performed to investigate the roles of MAPKs,
PI3-K/Akt, and NF-B in ATP-induced cPLA2 and COX-2 expression in VSMCs. These
protein expressions occurred at transcriptional and translational levels will be investigated by
cPLA2 and COX-2 promoter activity assays and and histone acetyltransferase activity in
ATP-induced cPLA2 and COX-2 expression in VSMCs. An increased understanding of signal
transduction pathways involved in ATP-induced cPLA2 and COX-2 expression in the vessels
may be of potential therapeutic value in the treatment of inflammatory disease included
artherosclerosis.
Project IDs
Project ID:PC9808-0526
External Project ID:NSC98-2320-B182-004-MY3
External Project ID:NSC98-2320-B182-004-MY3
Status | Finished |
---|---|
Effective start/end date | 01/08/09 → 31/07/10 |
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