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Up-regulation of thromboxane A(2) receptor expression by lipid soluble smoking particles through post-transcriptional mechanisms.

Zhang, Wei; Zhang, Yaping LU ; Edvinsson, Lars LU and Xu, Cang-Bao LU (2008) In Atherosclerosis 196(2). p.608-616
Abstract
Atherosclerosis is a key factor in vascular disease, and cigarette smoking is a well-known risk factor that may induce an inflammatory response and enhance plaque formation in arteries. Thromboxane (Tx) is one key inflammatory mediator involved in the pathogenesis of cardiovascular disease. The present study was designed to test if lipid soluble smoking particles (DSP) enhance TxA(2) receptor (TP) expression in rat mesenteric arteries, and if intracellular mitogen-activated protein kinase (MAPK) pathways play a role. Organ culture of rat mesenteric arteries in the presence of DSP (0.2 microl/ml for 24h) resulted in markedly elevated contractile responses to the Tx analog U46619, compared with the control DMSO. There was no increase in TP... (More)
Atherosclerosis is a key factor in vascular disease, and cigarette smoking is a well-known risk factor that may induce an inflammatory response and enhance plaque formation in arteries. Thromboxane (Tx) is one key inflammatory mediator involved in the pathogenesis of cardiovascular disease. The present study was designed to test if lipid soluble smoking particles (DSP) enhance TxA(2) receptor (TP) expression in rat mesenteric arteries, and if intracellular mitogen-activated protein kinase (MAPK) pathways play a role. Organ culture of rat mesenteric arteries in the presence of DSP (0.2 microl/ml for 24h) resulted in markedly elevated contractile responses to the Tx analog U46619, compared with the control DMSO. There was no increase in TP receptor mRNA expression, while the protein expression was significantly enhanced. This up-regulation was not affected by a general transcriptional inhibitor actinomycin D, but was almost completely abolished by cycloheximide, a general translational inhibitor. Dexamethasone, a glucocorticoid, manifested a potent inhibitory effect as well. These results suggest that the up-regulation of TP receptor occurs via post-transcriptional events, and mainly translation. This is supported by experiments with specific inhibitors for c-Jun-NH(2)-terminal kinase (SP600125), extracellular signal-regulated kinase 1 and 2 (PD98059 and U0126) and p38 (SB203580) that had no inhibitory effect on the up-regulation of TP receptors. Collectively, the results show that MAPK pathways are not involved in TP receptor up-regulation. Study on TP receptor mRNA stability showed that during organ culture, the TP receptor mRNA was stable in both DMSO and DSP group, but the latter elicited a tendency to stabilize the TP receptor mRNA at higher level. Thus, post-transcriptional mechanisms are responsible for the up-regulation of TP receptor by DSP, in which enhanced translation is the major cause of the elevated protein expression and the enhanced contraction. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Atherosclerosis
volume
196
issue
2
pages
608 - 616
publisher
Elsevier
external identifiers
  • wos:000253743800015
  • scopus:38349086656
ISSN
1879-1484
DOI
10.1016/j.atherosclerosis.2007.06.031
language
English
LU publication?
yes
id
c53970ba-cd6c-4c5c-8cff-184523b23d6a (old id 606781)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17706224&dopt=Abstract
date added to LUP
2008-07-31 14:29:39
date last changed
2017-04-09 03:31:57
@article{c53970ba-cd6c-4c5c-8cff-184523b23d6a,
  abstract     = {Atherosclerosis is a key factor in vascular disease, and cigarette smoking is a well-known risk factor that may induce an inflammatory response and enhance plaque formation in arteries. Thromboxane (Tx) is one key inflammatory mediator involved in the pathogenesis of cardiovascular disease. The present study was designed to test if lipid soluble smoking particles (DSP) enhance TxA(2) receptor (TP) expression in rat mesenteric arteries, and if intracellular mitogen-activated protein kinase (MAPK) pathways play a role. Organ culture of rat mesenteric arteries in the presence of DSP (0.2 microl/ml for 24h) resulted in markedly elevated contractile responses to the Tx analog U46619, compared with the control DMSO. There was no increase in TP receptor mRNA expression, while the protein expression was significantly enhanced. This up-regulation was not affected by a general transcriptional inhibitor actinomycin D, but was almost completely abolished by cycloheximide, a general translational inhibitor. Dexamethasone, a glucocorticoid, manifested a potent inhibitory effect as well. These results suggest that the up-regulation of TP receptor occurs via post-transcriptional events, and mainly translation. This is supported by experiments with specific inhibitors for c-Jun-NH(2)-terminal kinase (SP600125), extracellular signal-regulated kinase 1 and 2 (PD98059 and U0126) and p38 (SB203580) that had no inhibitory effect on the up-regulation of TP receptors. Collectively, the results show that MAPK pathways are not involved in TP receptor up-regulation. Study on TP receptor mRNA stability showed that during organ culture, the TP receptor mRNA was stable in both DMSO and DSP group, but the latter elicited a tendency to stabilize the TP receptor mRNA at higher level. Thus, post-transcriptional mechanisms are responsible for the up-regulation of TP receptor by DSP, in which enhanced translation is the major cause of the elevated protein expression and the enhanced contraction.},
  author       = {Zhang, Wei and Zhang, Yaping and Edvinsson, Lars and Xu, Cang-Bao},
  issn         = {1879-1484},
  language     = {eng},
  number       = {2},
  pages        = {608--616},
  publisher    = {Elsevier},
  series       = {Atherosclerosis},
  title        = {Up-regulation of thromboxane A(2) receptor expression by lipid soluble smoking particles through post-transcriptional mechanisms.},
  url          = {http://dx.doi.org/10.1016/j.atherosclerosis.2007.06.031},
  volume       = {196},
  year         = {2008},
}