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Renal and cardiovascular characterization of COX-2 knockdown mice
Francesca Seta1, Andrew D Chung, Patricia V Turner
1Department of Physiology, Queen's University, Kingston, Ontario, Canada.
Abstract:
Selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) increase the incidence of cardiovascular and cerebrovascular events. Complete disruption of the murine gene encoding COX-2 (Ptgs2) leads to renal developmental problems, as well as female reproductive anomalies and patent ductus arteriosus of variable penetrance in newborns, thus rendering this genetic approach difficult to compare with coxib administration. Here, we created hypomorphic Ptgs2 (COX-2(Neo/Neo)) mice in which COX-2 expression is suppressed to an extent similar to that achieved with coxibs, but not eliminated, in an attempt to circumvent these difficulties. In LPS-challenged macrophages and cytokine-stimulated endothelial cells obtained from COX-2(Neo/Neo) mice, COX-2 expression was reduced 70-90%, and these mice developed a mild renal phenotype compared with COX-2 mice possessing an active site mutation (COX-2(Y385F/Y385F)), with minimal signs of renal dysfunction as measured by FITC-inulin clearance and blood urea nitrogen. These COX-2 knockdown mice displayed an increased propensity for thrombogenesis compared with their wild-type (COX-2(+/+)) littermates observed by intravital microscopy in cremaster muscle arterioles upon ferric chloride challenge. Measurement of urinary prostanoid metabolites indicated that COX-2(Neo/Neo) mice produced 50% less prostacyclin but similar levels of PGE(2) and thromboxane compared with COX-2(+/+) mice in the absence of any blood pressure and ex vivo platelet aggregation abnormalities. COX-2(Neo/Neo) mice, therefore, provide a genetic surrogate of coxib therapy with disrupted prostacyclin biosynthesis that predisposes to induced arterial thrombosis.
Insights
Selective cyclooxygenase-2 (COX-2) inhibitors cause cardiovascular risks. New COX-2(Neo/Neo) mice mimic coxib effects, showing increased thrombosis due to reduced prostacyclin, not other prostanoids.
Area of Science:
- Biomedical Science
- Genetics
- Cardiovascular Research
Background:
- Selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) are linked to cardiovascular and cerebrovascular events.
- Complete COX-2 gene knockout in mice causes developmental issues, complicating comparisons with coxib administration.
Purpose of the Study:
- To create a mouse model (COX-2(Neo/Neo)) that mimics the suppressed COX-2 expression of coxib therapy without complete gene elimination.
- To investigate the cardiovascular and renal effects of reduced COX-2 expression.
Main Methods:
- Generated hypomorphic Ptgs2 (COX-2(Neo/Neo)) mice with suppressed COX-2 expression.
- Assessed COX-2 expression in macrophages and endothelial cells.
- Evaluated renal function using FITC-inulin clearance and blood urea nitrogen.
- Observed thrombogenesis in cremaster muscle arterioles via intravital microscopy after ferric chloride challenge.
- Measured urinary prostanoid metabolites (prostacyclin, PGE2, thromboxane).
Main Results:
- COX-2(Neo/Neo) mice exhibited 70-90% reduced COX-2 expression.
- These mice showed a mild renal phenotype with minimal dysfunction.
- COX-2(Neo/Neo) mice demonstrated an increased propensity for arterial thrombosis compared to wild-type littermates.
- Urinary prostanoid analysis revealed 50% less prostacyclin, but similar PGE2 and thromboxane levels, without affecting blood pressure or platelet aggregation.
Conclusions:
- COX-2(Neo/Neo) mice serve as a genetic model for coxib therapy, demonstrating disrupted prostacyclin biosynthesis.
- This model highlights how reduced prostacyclin, mimicking coxib action, predisposes to induced arterial thrombosis.
- The findings link selective COX-2 inhibition to thrombotic events through prostacyclin pathway disruption.
