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Aspirin reduces the prothrombotic activity of C-reactive protein
E Grad1, M Golomb, N Koroukhov
1Heart Research Centre, Hadassah Hebrew University Medical Centre, Jerusalem, Israel.
Insights
C-reactive protein (CRP) promotes blood clots by altering prostanoid metabolism. Aspirin treatment in CRP-transgenic mice counteracted this effect, suggesting aspirin may limit cardiovascular risk associated with elevated CRP.
Area of Science:
- Cardiovascular biology
- Thrombosis research
- Pharmacology
Background:
- C-reactive protein (CRP) is a known risk marker for vascular disease.
- Previous research indicates CRP possesses prothrombotic activity, potentially impairing normal blood clot regulation.
- The interplay between CRP, vascular injury, and thromboregulation requires further investigation.
Purpose of the Study:
- To investigate the antithrombotic effect of aspirin in mice genetically engineered to express human CRP (CRPtg mice).
- To elucidate the mechanisms by which CRP influences prostanoid metabolism in vivo and in vitro.
- To assess the impact of CRP on vascular injury response and aspirin's therapeutic potential.
Main Methods:
- Photochemical injury was induced in the carotid arteries of CRPtg mice and wild-type controls.
- Aspirin treatment (30 mg kg(-1) day(-1)) was administered to assess its effect on thrombosis time.
- Prostanoid metabolism pathways, including cyclo-oxygenase 2 (COX-2), prostaglandin I2 (PGI2) synthase, and thromboxane receptor expression, were analyzed in injured arteries.
- In vitro studies utilized human umbilical vein endothelial cells (HUVECs) and smooth muscle cells incubated with human recombinant CRP.
Main Results:
- Aspirin significantly slowed accelerated thrombosis in CRPtg mice compared to untreated CRPtg mice and wild-type controls.
- Vascular injury differentially modulated prostanoid metabolism in CRPtg and wild-type mice, with suppressed PGI2 and increased thromboxane receptor expression in CRPtg mice.
- Aspirin treatment normalized PGI2 biosynthesis differences between CRPtg and wild-type mice.
- In vitro, CRP suppressed PGI2 synthase and increased thromboxane receptor levels in HUVECs, but not in smooth muscle cells.
Conclusions:
- CRP actively modulates prostanoid metabolism, favoring conditions that lead to vascular occlusion (blood clots).
- Elevated CRP levels may exacerbate cardiovascular risks, particularly when combined with selective COX-2 inhibitors.
- Aspirin demonstrates potential in mitigating the prothrombotic risk mediated by CRP.
Aim:
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.
Methods And 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.
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