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Importance of MAPK and PKC in cerebrovascular endothelin receptor changes

Henriksson, Marie LU (2006)
Abstract
Endothelin is a vasoactive peptide that exerts its effect through two receptors; the endothelin type A (ETA) and type B (ETB) receptor. The contractile ETA receptor is localized on smooth muscle cells in the vascular wall, while the ETB receptors are mainly situated on endothelial cells, mediating vasodilatation. The endothelin system is involved in several pathophysiological conditions, such as atherosclerosis and ischemic stroke.



Previous studies have shown an upregulation of contractile ETB receptors in the ipsilateral middle cerebral artery (MCA) after experimental focal ischemia and a similar upregulation is also seen after organ culture of MCA. Furthermore, studies have shown an involvement of protein kinase C... (More)
Endothelin is a vasoactive peptide that exerts its effect through two receptors; the endothelin type A (ETA) and type B (ETB) receptor. The contractile ETA receptor is localized on smooth muscle cells in the vascular wall, while the ETB receptors are mainly situated on endothelial cells, mediating vasodilatation. The endothelin system is involved in several pathophysiological conditions, such as atherosclerosis and ischemic stroke.



Previous studies have shown an upregulation of contractile ETB receptors in the ipsilateral middle cerebral artery (MCA) after experimental focal ischemia and a similar upregulation is also seen after organ culture of MCA. Furthermore, studies have shown an involvement of protein kinase C (PKC) and extracellular signal-regulated kinases (ERK) 1/2 in ischemia.



The aim of this thesis was to further elucidate the mechanisms underlying this receptor upregulation process, both in experimental ischemia and in organ culture of rat MCA.



The results from the organ culture studies (paper I-III) show that the ETB receptor upregulation is time-dependent, reaching a maximum after 24 hours of organ culture. By adding inhibitors of PKC and ERK1/2 pathways to the culture medium, the ETB receptor upregulation was attenuated.



In the experimental model of ischemia (paper IV-V), we administered PKC and ERK1/2 inhibitors to the rats in conjuction with the ischemic insult. Both inhibitors diminished the ETB receptor responses, as well as decreasing brain damage and improving neurological function.



In conclusion, the results of this thesis may provide a new perspective on possible



mechanisms of actions of PKC and ERK in cerebral ischemia. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor McCulloch, James, University of Edinburgh, UK
organization
publishing date
type
Thesis
publication status
published
subject
keywords
farmakognosi, farmaci, toxikologi, toxicology, pharmacy, pharmacognosy, Pharmacological sciences, Kardiovaskulära systemet, Cardiovascular system, Fysiologi, Physiology, cerebral arteries, ischemia, receptors, endothelin, Farmakologi
pages
110 pages
publisher
Department of Clinical Sciences, Lund University
defense location
Segerfalksalen, Wallenberg Neuroscience Centre, Lund, Sweden
defense date
2006-04-22 10:00:00
ISBN
91-85481-70-x
language
English
LU publication?
yes
additional info
M Henriksson, E Stenman and L Edvinsson. 2003. Intracellular pathways involved in upregulation of vascular endothelin type B receptors in cerebral arteries of the rat. Stroke, vol 34 pp 1479-83.
M Henriksson, C Xu and L Edvinsson. 2004. Importance of ERK1/2 in upregulation of endothelin type B receptors in cerebral arteries. British journal of pharmacology, vol 142 pp 1155-61.
M Henriksson, P Vikman, E Stenman, S Beg and L Edvinsson. 2006. The role of PKC in cerebrovascular endothelin ETB receptor upregulation. (submitted)
M Henriksson, E Stenman, P Vikman and L Edvinsson. 2006. MEK1/2 inhibition attenuates vascular ETA and ETB upregulation after cerebral ischemia. (submitted)
M Henriksson, P Vikman, E Stenman and L Edvinsson. 2006. PKC inhibition attenuates vascular ETB receptor upregulation and decreases brain damage after cerebral ischemia. (manuscript)
id
c661e2b6-8b28-464e-b4a4-11be00ab98f9 (old id 546496)
date added to LUP
2016-04-01 16:08:04
date last changed
2018-11-21 20:39:01
@phdthesis{c661e2b6-8b28-464e-b4a4-11be00ab98f9,
  abstract     = {{Endothelin is a vasoactive peptide that exerts its effect through two receptors; the endothelin type A (ETA) and type B (ETB) receptor. The contractile ETA receptor is localized on smooth muscle cells in the vascular wall, while the ETB receptors are mainly situated on endothelial cells, mediating vasodilatation. The endothelin system is involved in several pathophysiological conditions, such as atherosclerosis and ischemic stroke.<br/><br>
<br/><br>
Previous studies have shown an upregulation of contractile ETB receptors in the ipsilateral middle cerebral artery (MCA) after experimental focal ischemia and a similar upregulation is also seen after organ culture of MCA. Furthermore, studies have shown an involvement of protein kinase C (PKC) and extracellular signal-regulated kinases (ERK) 1/2 in ischemia.<br/><br>
<br/><br>
The aim of this thesis was to further elucidate the mechanisms underlying this receptor upregulation process, both in experimental ischemia and in organ culture of rat MCA.<br/><br>
<br/><br>
The results from the organ culture studies (paper I-III) show that the ETB receptor upregulation is time-dependent, reaching a maximum after 24 hours of organ culture. By adding inhibitors of PKC and ERK1/2 pathways to the culture medium, the ETB receptor upregulation was attenuated.<br/><br>
<br/><br>
In the experimental model of ischemia (paper IV-V), we administered PKC and ERK1/2 inhibitors to the rats in conjuction with the ischemic insult. Both inhibitors diminished the ETB receptor responses, as well as decreasing brain damage and improving neurological function.<br/><br>
<br/><br>
In conclusion, the results of this thesis may provide a new perspective on possible<br/><br>
<br/><br>
mechanisms of actions of PKC and ERK in cerebral ischemia.}},
  author       = {{Henriksson, Marie}},
  isbn         = {{91-85481-70-x}},
  keywords     = {{farmakognosi; farmaci; toxikologi; toxicology; pharmacy; pharmacognosy; Pharmacological sciences; Kardiovaskulära systemet; Cardiovascular system; Fysiologi; Physiology; cerebral arteries; ischemia; receptors; endothelin; Farmakologi}},
  language     = {{eng}},
  publisher    = {{Department of Clinical Sciences, Lund University}},
  school       = {{Lund University}},
  title        = {{Importance of MAPK and PKC in cerebrovascular endothelin receptor changes}},
  url          = {{https://lup.lub.lu.se/search/files/4578281/546497.pdf}},
  year         = {{2006}},
}