Abstract 15733: Inducible Postnatal Deletion Of COX-2 Accelerates Atherogenesis In Mice
Background: Nonsteroidal anti-inflammatory drugs confer a cardiovascular hazard attributable to suppression of cyclooxygenase (COX)-2 derived prostacyclin (PGI2). A predisposition to thrombogenesis, hypertension and heart failure - reflective of the human phenotype - can be recapitulated by disruption of this pathway in mice. However, although randomized trials of COX-2 inhibitors are consistent with risk transformation in humans and deletion of the PGI2 receptor accelerates atherogenesis in mice, inhibition and conventional deletion of COX-2 have yielded conflicting results. Given the importance of COX-2 in development and the contrasting products of COX-2 formed by shifting cells prominent in the evolving plaque, we generated a mouse model in which timed, postnatal global deletion of COX-2 could be accomplished.
Method and results: Inducible deletion of COX-2 (Ind.COX-2 KO) was achieved with Cre-ERTM mice, resulting in ~95% suppression of peritoneal macrophage prostaglandin formation. In contrast to conventional COX-2 KOs, Ind.COX-2 KOs bypassed cardiorenal lesions during development. Atherogenesis was accelerated in both genders when Ind.COX-2 KO was crossed onto a hyperlipidemic ApoE KO background. COX-2 deletion promotes leukocyte infiltration, facilitates dedifferentiation of vascular smooth muscle cells from a “contractile” to a “synthetic” state as measured by loss of α-smooth muscle cell actin and upregulation of vascular cell adhesion molecule-1. While suppression of COX-2 derived PGI2 can explain this phenotype, we addressed the possibility that rediversion of arachidonic acid (AA) to 5-lipoxygenase (LO) pathways might also contribute to this hazard. Disruption of 5-LO activating protein (FLAP) alone did not alter atherogenesis, but in Ind.COX-2/FLAP/ApoE triple KOs, the acceleration of atherogenesis due to COX-2 deletion was attenuated by concomitant FLAP deletion.
Conclusion: Avoidance of the confounding effects of COX-2 disruption during development reveals the constraint exerted by COX-2 derived PGI2 on atherogenesis. However, although disruption of FLAP has no direct effect on atherogenesis, rediversion to 5-LO products exacerbates the impact of PGI2 suppression on atherogenesis in hyperlipidemic mice.
- © 2011 by American Heart Association, Inc.