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Upregulation of contractile endothelin type B receptors by lipid-soluble cigarette smoking particles in rat cerebral arteries via activation of MAPK

Sandhu, Hardip; Xu, Cang-Bao LU and Edvinsson, Lars LU (2010) In Toxicology and Applied Pharmacology 249(1). p.25-32
Abstract
Cigarette smoke exposure increases the risk of stroke. However, the underlying molecular mechanisms are poorly understood. Endothelin system plays key roles in the pathogenesis of stroke. The present study was designed to examine if lipid-soluble (dimethyl sulfoxide-soluble) cigarette smoke particles (DSP) induces upregulation of contractile endothelin type B (ETB) receptors in rat cerebral arteries and if activation of mitogen activated protein kinase (MAPK) and nuclear factor-kappaB (NF-kappa B) mediate the upregulation of contractile endothelin receptors in the cerebral arteries. Rat middle cerebral arteries were isolated and organ cultured in serum free medium for 24 h in the presence of DSP with or without specific inhibitors: MEK... (More)
Cigarette smoke exposure increases the risk of stroke. However, the underlying molecular mechanisms are poorly understood. Endothelin system plays key roles in the pathogenesis of stroke. The present study was designed to examine if lipid-soluble (dimethyl sulfoxide-soluble) cigarette smoke particles (DSP) induces upregulation of contractile endothelin type B (ETB) receptors in rat cerebral arteries and if activation of mitogen activated protein kinase (MAPK) and nuclear factor-kappaB (NF-kappa B) mediate the upregulation of contractile endothelin receptors in the cerebral arteries. Rat middle cerebral arteries were isolated and organ cultured in serum free medium for 24 h in the presence of DSP with or without specific inhibitors: MEK specific (U0126), p38 specific (SB202190). JNK specific (SP600125), NF-kappa B specific (BMS-345541) or (IMD-0354), transcription inhibitor (actinomycin D), or translation blocker (cycloheximide). Contractile responses to the ETB receptor agonist sarafotoxin 6c were investigated by a sensitive myograph. The expression of the ETB receptors were studied at mRNA and protein levels using quantitative real time PCR and immunohistochemistry, respectively. Results show that organ culture per se induced transcriptional upregulation of contractile ETB receptors in the cerebral vascular smooth muscle cells. This upregulation was further increased at the translational level by addition of DSP to the organ culture, but this increase was not seen by addition of nicotine or water-soluble cigarette smoke particles to the organ culture. The increased upregulation of contractile ETB receptors by DSP was abrogated by U0126. SP600125, actinomycin D. and cycloheximide, suggesting that the underlying molecular mechanisms involved in this process include activation of MEK and JNK MAPK-mediated transcription and translation of new contractile ETB receptors. Thus, the MAPK-mediated upregulation of contractile ETB receptors in cerebral arteries might be a pharmacological target for the treatment of smoke-associated cerebral vascular disease like stroke. (C) 2010 Elsevier Inc. All rights reserved. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Lipid-soluble cigarette smoking particles, Vascular smooth muscle cells, Organ culture, Cerebral arteries, Endothelin ETB receptor, MAPK
in
Toxicology and Applied Pharmacology
volume
249
issue
1
pages
25 - 32
publisher
Academic Press
external identifiers
  • wos:000283677000004
  • scopus:77957869032
ISSN
1096-0333
DOI
10.1016/j.taap.2010.08.010
language
English
LU publication?
yes
id
10a70282-6337-4217-8df7-a8bcede79946 (old id 1718915)
date added to LUP
2010-12-23 10:17:16
date last changed
2018-07-15 03:54:59
@article{10a70282-6337-4217-8df7-a8bcede79946,
  abstract     = {Cigarette smoke exposure increases the risk of stroke. However, the underlying molecular mechanisms are poorly understood. Endothelin system plays key roles in the pathogenesis of stroke. The present study was designed to examine if lipid-soluble (dimethyl sulfoxide-soluble) cigarette smoke particles (DSP) induces upregulation of contractile endothelin type B (ETB) receptors in rat cerebral arteries and if activation of mitogen activated protein kinase (MAPK) and nuclear factor-kappaB (NF-kappa B) mediate the upregulation of contractile endothelin receptors in the cerebral arteries. Rat middle cerebral arteries were isolated and organ cultured in serum free medium for 24 h in the presence of DSP with or without specific inhibitors: MEK specific (U0126), p38 specific (SB202190). JNK specific (SP600125), NF-kappa B specific (BMS-345541) or (IMD-0354), transcription inhibitor (actinomycin D), or translation blocker (cycloheximide). Contractile responses to the ETB receptor agonist sarafotoxin 6c were investigated by a sensitive myograph. The expression of the ETB receptors were studied at mRNA and protein levels using quantitative real time PCR and immunohistochemistry, respectively. Results show that organ culture per se induced transcriptional upregulation of contractile ETB receptors in the cerebral vascular smooth muscle cells. This upregulation was further increased at the translational level by addition of DSP to the organ culture, but this increase was not seen by addition of nicotine or water-soluble cigarette smoke particles to the organ culture. The increased upregulation of contractile ETB receptors by DSP was abrogated by U0126. SP600125, actinomycin D. and cycloheximide, suggesting that the underlying molecular mechanisms involved in this process include activation of MEK and JNK MAPK-mediated transcription and translation of new contractile ETB receptors. Thus, the MAPK-mediated upregulation of contractile ETB receptors in cerebral arteries might be a pharmacological target for the treatment of smoke-associated cerebral vascular disease like stroke. (C) 2010 Elsevier Inc. All rights reserved.},
  author       = {Sandhu, Hardip and Xu, Cang-Bao and Edvinsson, Lars},
  issn         = {1096-0333},
  keyword      = {Lipid-soluble cigarette smoking particles,Vascular smooth muscle cells,Organ culture,Cerebral arteries,Endothelin ETB receptor,MAPK},
  language     = {eng},
  number       = {1},
  pages        = {25--32},
  publisher    = {Academic Press},
  series       = {Toxicology and Applied Pharmacology},
  title        = {Upregulation of contractile endothelin type B receptors by lipid-soluble cigarette smoking particles in rat cerebral arteries via activation of MAPK},
  url          = {http://dx.doi.org/10.1016/j.taap.2010.08.010},
  volume       = {249},
  year         = {2010},
}