Gallic acid antagonizes P-selectin-mediated platelet-leukocyte interactions: implications for the French paradox.
BACKGROUND
Current paradigm attributes the low incidence of cardiovascular disorders in Mediterranean countries despite a high saturated fat intake, the "French paradox," to the antioxidant capacity of red wine polyphenols. Conceivably, other antiinflammatory pathways may contribute to at least a similar extent to the atheroprotective activity of these polyphenols. We have investigated whether gallic acid (GA), an abundant red wine polyphenol, modulates the activity of P-selectin, an adhesion molecule that is critically involved in the recruitment of inflammatory cells to the vessel wall and thus in atherosclerosis.


RESULTS
GA potently inhibited the binding of a peptide antagonist (IC50, 7.2 micromol/L) and biotin-PAA-Le(a)-SO3H, an established high-affinity ligand, to P-selectin (IC50, 85 micromol/L). Under dynamic flow conditions, GA markedly and dose dependently attenuated the rolling of monocytic HL60 cells over P-selectin-transfected Chinese hamster ovary cells (EC50, 14.5 micromol/L) while increasing the velocity of P-selectin-dependent rolling of human blood leukocytes over a platelet monolayer. In vivo tests established that GA administration to normolipidemic C57/Bl6 and aged atherosclerotic apolipoprotein E-deficient mice impaired the baseline rolling of conjugates between activated platelets and circulating monocytes over femoral vein endothelium, as judged by online video microscopy (ED50, 1.7+/-0.3 and 1.5+/-0.4 mg x kg(-1) x h(-1), respectively).


CONCLUSIONS
Our findings provide a solid mechanistic foundation through which GA intervenes in major inflammatory pathobiologies by binding and antagonizing P-selectin.
Appeldoorn
Chantal C M
CC
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Gorlaeus Laboratories, Leiden, The Netherlands.
Bonnefoy
Arnaud
A
Lutters
Bianca C H
BC
Daenens
Kim
K
van Berkel
Theo J C
TJ
Hoylaerts
Marc F
MF
Biessen
Erik A L
EA
D000178:Acrylamides / Q000494:pharmacology; D000180:Acrylic Resins; D000595:Amino Acid Sequence; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001667:Binding, Competitive; D001710:Biotin / Q000031:analogs & derivatives* / Q000494:pharmacology; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects*; D016466:CHO Cells / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003094:Collagen / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004036:Diet, Atherogenic; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology; D005268:Femoral Vein / Q000473:pathology; D005707:Gallic Acid / Q000494:pharmacology*; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood; D020128:Inhibitory Concentration 50; D017136:Ion Transport; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects*; D007983:Lewis Blood Group Antigens; D051379:Mice; D008810:Mice, Inbred C57BL; D018715:Microscopy, Video; D008969:Molecular Sequence Data; D019007:P-Selectin / Q000187:drug effects*; D010455:Peptides; D010973:Platelet Adhesiveness / Q000187:drug effects*; D014920:Wine / Q000032:analysis; D000099166:Polyacrylamides
D000178:Acrylamides; D000180:Acrylic Resins; D000975:Antioxidants; D001057:Apolipoproteins E; D001710:Biotin; D002118:Calcium; D002352:Carrier Proteins; D003094:Collagen; D005707:Gallic Acid; D007983:Lewis Blood Group Antigens; D019007:P-Selectin; D010455:Peptides; C501518:TM11 peptide; C501519:biotinylated sulfo-Lewis A derivatized polyacrylamide; D000099166:Polyacrylamides