Objective— The role of myeloid cell cyclooxygenase-2 (COX-2) in the progression of atherosclerosis has not been clearly defined.

Methods and Results— We investigated the role of COX-2 expressed in the myeloid lineage in the development of atherosclerosis using a myeloid-specific COX-2^−/− (COX-2^−M/−M) mouse on a hyperlipidemic apolipoprotein (apo) E^−/− background (COX-2^−M/−M/apoE^−/−). Myeloid COX-2 depletion resulted in significant attenuation of acute inflammation corresponding with decreased PGE₂ levels in an air pouch model. COX-2 depletion in myeloid cells did not influence development of atherosclerosis in COX-2^−M/−M/apoE^−/− when compared to apoE^−/− littermates fed either chow or western diets. The unanticipated lack of contribution of myeloid COX-2 to the development atherosclerosis is not attributable to altered maintenance, differentiation, or mobilization of myeloid and lymphoid populations. Moreover, myeloid COX-2 depletion resulted in unaltered serum prostanoid levels and cellular composition of atherosclerotic lesions of COX-2^−M/−M/apoE^−/− mice.

Conclusions— Our results suggest that COX-2 expression in myeloid cells, including macrophages, does not influence the development of atherosclerosis in mice.