P-selectin as a candidate target in atherosclerosis.
P-selectin is of critical importance in early atherogenesis by initiating leukocyte rolling at the site of endothelial injury. In order to validate P-selectin as a candidate target for the development of anti-atherogenic strategies, we wanted to obtain quantitative information on P-selectin expression, and identify novel peptide-based lead structures that interact with P-selectin. P-selectin mRNA expression in the aortic arch and in other tissues of apoE-deficient (apoE-/-) mice was determined by real-time PCR technology. P-selectin mRNA expression of apoE-/- mice increased steadily with age to levels 14-fold higher than that of control animals. The onset and level of P-selectin expression correlated well with the extent of lesion development, and was more specific for atherosclerotic tissue as compared with other adhesion molecules. Phage display technology was used to obtain novel P-selectin antagonists. Phage display selections resulted in the isolation of a highly P-selectin-specific phage clone. Synthetic peptide-equivalents of this clone displaced the binding of the parent phage and antagonized the binding of a sialyl Lewis(x) analogue to P-selectin. In conclusion, P-selectin expression correlates with early and advanced atherosclerotic lesion development. P-selectin ligands, like the lead structure we have developed here, can therefore be considered as promising tools to identify, target or antagonize P-selectin function within the chronically inflamed arterial wall.
Molenaar
Tom J M
TJ
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
Twisk
Jaap
J
de Haas
Sonja A M
SA
Peterse
Niels
N
Vogelaar
Bram J C P
BJ
van Leeuwen
Steven H
SH
Michon
Ingrid N
IN
van Berkel
Theo J C
TJ
Kuiper
Johan
J
Biessen
Erik A L
EA
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000378:metabolism; D001161:Arteriosclerosis / Q000378:metabolism* / Q000517:prevention & control; D018450:Disease Progression; D015195:Drug Design; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism*; D019151:Peptide Library; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism
D001057:Apolipoproteins E; D019007:P-Selectin; D019151:Peptide Library; D010455:Peptides; D012333:RNA, Messenger