Aspirin reduces the prothrombotic activity of C-reactive protein.
OBJECTIVE
C-reactive protein (CRP) is a risk marker and a potential modulator of vascular disease. Previous studies support a prothrombotic activity of CRP, with impaired thromboregulation. The present study examined the antithrombotic effect of aspirin in mice transgenic for human CRP (CRPtg mice). Mechanistic investigations further elucidated the effect of CRP on prostanoid metabolism in vivo and in vitro.


RESULTS
Administration of aspirin (30 mg kg(-1) day(-1)) to CRPtg mice slowed the accelerated thrombosis after photochemical injury to the carotid (99 +/- 32 vs. 45 +/- 24 min and 75 +/- 23 vs. 82 +/- 26 min in wild-type mice vs. CRPtg mice, without and following aspirin treatment, respectively). Vascular injury modulated the expression of key pathways in prostanoid metabolism differently in CRPtg mice and wild-type mice. Suppression of cyclo-oxygenase 2 (COX-2)-derived metabolism with suppression of prostaglandin I2 (PGI2) synthase and PGI2 metabolism was recorded in the injured artery with increased thromboxane receptor expression. Aspirin therapy reduced the difference in PGI2 biosynthesis between CRPtg mice and wild-type mice. In vitro studies in human-derived cells further supported these findings. Incubation of human umbilical vein endothelial cells (HUVECs) with human recombinant CRP (5 microg mL(-1)) suppressed PGI2 synthase expression and significantly increased thromboxane receptor levels. Incubation of smooth muscle cells with CRP did not affect prostanoid expression.


CONCLUSIONS
CRP modulates prostanoid metabolism to favor vascular occlusion. Elevated CRP levels might predispose to the cardiovascular hazard conferred by selective COX-2 inhibitors, and the risk mediated by CRP may be limited by aspirin.
Grad
E
E
Heart Research Centre, Hadassah Hebrew University Medical Centre, Jerusalem, Israel.
Golomb
M
M
Koroukhov
N
N
Lawson
J A
JA
Lotan
C
C
Fitzgerald
G A
GA
Danenberg
H D
HD
D000818:Animals; D001241:Aspirin / Q000008:administration & dosage / Q000494:pharmacology*; D002097:C-Reactive Protein / Q000494:pharmacology*; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D004347:Drug Interactions; D004730:Endothelium, Vascular / Q000166:cytology; D011464:Epoprostenol / Q000378:metabolism*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000032:analysis; D051379:Mice; D008822:Mice, Transgenic; D017482:Receptors, Thromboxane / Q000032:analysis; D013927:Thrombosis / Q000139:chemically induced* / Q000188:drug therapy* / Q000517:prevention & control
D017482:Receptors, Thromboxane; D002097:C-Reactive Protein; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase; D001241:Aspirin