Advanced

Genetic studies on cardiovascular disease - identification of novel drug targets

Amisten, Stefan LU (2007)
Abstract
The aim of this thesis was to identify novel potential drug targets of cardiovascular disease with a focus on G-protein coupled receptors.



We identified a common genetic variant of the ATP receptor P2Y11, where an alanine is substituted with a threonine at position 87 of the P2Y11 receptor that increases the risk of developing acute myocardial infarction. Also, the Thr-87 variant of P2Y11 is associated with elevated serum concentrations of C-reactive protein. In CHO cells, ATP?S stimulated recombinant P2Y11 Thr-87 displayed a reduced cAMP response compared to the P2Y11 Ala-87 variant. We hypothesize that a loss of a protective mechanism mediated by P2Y11 cAMP signaling is involved in the increased risk of myocardial... (More)
The aim of this thesis was to identify novel potential drug targets of cardiovascular disease with a focus on G-protein coupled receptors.



We identified a common genetic variant of the ATP receptor P2Y11, where an alanine is substituted with a threonine at position 87 of the P2Y11 receptor that increases the risk of developing acute myocardial infarction. Also, the Thr-87 variant of P2Y11 is associated with elevated serum concentrations of C-reactive protein. In CHO cells, ATP?S stimulated recombinant P2Y11 Thr-87 displayed a reduced cAMP response compared to the P2Y11 Ala-87 variant. We hypothesize that a loss of a protective mechanism mediated by P2Y11 cAMP signaling is involved in the increased risk of myocardial infarction seen in the AMI case-control study.



Polymorphisms forming a H2 haplotype of the ADP receptor P2Y12 have been linked to an increased platelet response to ADP and increased risks of atherosclerosis and peripheral arterial disease. We show that a polymorphism of the P2Y13 gene, causing a methionine to threonine substitution at position 158 of the P2Y13 receptor, is in complete linkage disequilibrium with the P2Y12 H2 haplotype. However, in three separate populations, we found no association between the P2Y12 H2 haplotype/P2Y13 Thr-158 polymorphisms and myocardial infarction, type 2 diabetes or any examined cardiovascular risk factor.



G-protein coupled receptors are important regulators of platelet activation. Using microarray, we identified several G-protein coupled receptors in platelets whose expression in platelets has not previously been known. To illustrate our findings, we demonstrate for the first time adenosine A2B receptor mediated inhibition of platelet activation.



Finally, using a unique in vitro model, we examined the molecular response to the implantation of bare metal and drug-eluting cardiovascular stents into human arteries. We found several differentially expressed genes involved in the regulation of inflammation, endothelial cell function, platelet activation and cellular proliferation. We hope that our model will increase the understanding of the processes involved in restenosis and late stent thrombosis associated with bare metal and drug-eluting stents and that our model may be useful in the development of next generation drug eluting stents. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Docent Adner, Mikael, Karolinska Institute
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Genetics, Medicin (människa och djur), Medicine (human and vertebrates), platelet, single nucleotide polymorphism, myocardial infarction, stent, G-protein coupled receptor, P2Y, cytogenetics, Genetik, cytogenetik, Cardiovascular system, Kardiovaskulära systemet
publisher
Cardiology
defense location
Segerfalksalen Wallenberg Neurocentrum Sölvegatan 19 Lund
defense date
2007-11-16 09:00
ISSN
1652-8220
ISBN
978-91-85897-19-3
language
English
LU publication?
yes
id
b53d5c02-044a-4401-a1e7-8bc8b2437a00 (old id 599265)
date added to LUP
2007-11-12 19:17:55
date last changed
2016-09-19 08:44:53
@phdthesis{b53d5c02-044a-4401-a1e7-8bc8b2437a00,
  abstract     = {The aim of this thesis was to identify novel potential drug targets of cardiovascular disease with a focus on G-protein coupled receptors.<br/><br>
<br/><br>
We identified a common genetic variant of the ATP receptor P2Y11, where an alanine is substituted with a threonine at position 87 of the P2Y11 receptor that increases the risk of developing acute myocardial infarction. Also, the Thr-87 variant of P2Y11 is associated with elevated serum concentrations of C-reactive protein. In CHO cells, ATP?S stimulated recombinant P2Y11 Thr-87 displayed a reduced cAMP response compared to the P2Y11 Ala-87 variant. We hypothesize that a loss of a protective mechanism mediated by P2Y11 cAMP signaling is involved in the increased risk of myocardial infarction seen in the AMI case-control study.<br/><br>
<br/><br>
Polymorphisms forming a H2 haplotype of the ADP receptor P2Y12 have been linked to an increased platelet response to ADP and increased risks of atherosclerosis and peripheral arterial disease. We show that a polymorphism of the P2Y13 gene, causing a methionine to threonine substitution at position 158 of the P2Y13 receptor, is in complete linkage disequilibrium with the P2Y12 H2 haplotype. However, in three separate populations, we found no association between the P2Y12 H2 haplotype/P2Y13 Thr-158 polymorphisms and myocardial infarction, type 2 diabetes or any examined cardiovascular risk factor.<br/><br>
<br/><br>
G-protein coupled receptors are important regulators of platelet activation. Using microarray, we identified several G-protein coupled receptors in platelets whose expression in platelets has not previously been known. To illustrate our findings, we demonstrate for the first time adenosine A2B receptor mediated inhibition of platelet activation.<br/><br>
<br/><br>
Finally, using a unique in vitro model, we examined the molecular response to the implantation of bare metal and drug-eluting cardiovascular stents into human arteries. We found several differentially expressed genes involved in the regulation of inflammation, endothelial cell function, platelet activation and cellular proliferation. We hope that our model will increase the understanding of the processes involved in restenosis and late stent thrombosis associated with bare metal and drug-eluting stents and that our model may be useful in the development of next generation drug eluting stents.},
  author       = {Amisten, Stefan},
  isbn         = {978-91-85897-19-3},
  issn         = {1652-8220},
  keyword      = {Genetics,Medicin (människa och djur),Medicine (human and vertebrates),platelet,single nucleotide polymorphism,myocardial infarction,stent,G-protein coupled receptor,P2Y,cytogenetics,Genetik,cytogenetik,Cardiovascular system,Kardiovaskulära systemet},
  language     = {eng},
  publisher    = {Cardiology},
  school       = {Lund University},
  title        = {Genetic studies on cardiovascular disease - identification of novel drug targets},
  year         = {2007},
}