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A Model of Disturbed Flow-Induced Atherosclerosis in Mouse Carotid Artery by Partial Ligation and a Simple Method of RNA Isolation from Carotid Endothelium
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Published on: June 22, 2010

Disruption of the 5-lipoxygenase pathway attenuates atherogenesis consequent to COX-2 deletion in mice

Zhou Yu1, Irene Crichton, Soon Yew Tang

  • 1Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Proceedings of the National Academy of Sciences of the United States of America
|April 12, 2012
PubMed

Insights

Nonsteroidal anti-inflammatory drugs (NSAIDs) increase cardiovascular risk by suppressing cyclooxygenase 2 (COX-2). Postnatal COX-2 deletion in mice accelerated atherosclerosis, suggesting a mechanism for NSAID-related cardiovascular hazards.

Area of Science:

  • Cardiovascular Science
  • Inflammation Research
  • Pharmacology

Background:

  • Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with cardiovascular risk, partly due to suppression of cyclooxygenase 2 (COX-2)-derived prostacyclin (PGI(2)).
  • Conventional COX-2 knockout mice exhibit developmental defects, limiting their use in studying chronic NSAID effects.
  • Understanding the role of COX-2 in atherogenesis is crucial for mitigating NSAID-induced cardiovascular hazards.

Purpose of the Study:

  • To investigate the role of postnatal COX-2 deletion in promoting atherosclerosis.
  • To elucidate the mechanistic link between COX-2 inhibition and cardiovascular risk associated with NSAID use.

Main Methods:

  • Developed mice with postnatal deletion of COX-2 to bypass developmental issues.
  • Crossed these mice with ApoE-deficient hyperlipidemic mice to study atherogenesis.
  • Analyzed atherosclerotic lesions for leukocyte infiltration and vascular smooth muscle cell markers.
  • Examined peritoneal macrophages for prostanoid and lipoxygenase product formation.
  • Investigated the effect of 5-lipoxygenase activating protein (FLAP) deletion on atherogenesis.

Main Results:

  • Postnatal COX-2 deletion accelerated atherosclerosis in hyperlipidemic mice, with increased leukocyte infiltration and altered vascular smooth muscle cell phenotype.
  • COX-2 deletion led to suppressed COX-2-derived prostanoids and increased 5-lipoxygenase products in macrophages, indicating substrate rediversion.
  • Deletion of FLAP did not affect atherogenesis but attenuated the pro-atherogenic effects of COX-2 deletion.

Conclusions:

  • Postnatal COX-2 deletion promotes atherogenesis, providing a mechanistic explanation for the cardiovascular hazard of chronic NSAID use.
  • The findings suggest that NSAIDs may increase cardiovascular risk, particularly in individuals with pre-existing low risk.
  • Co-inhibition of FLAP may represent a strategy to mitigate NSAID-associated cardiovascular risks.

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