Abstract 1161: Cyclooxygenase 2 Inhibitors Reduce Hyaluronan Synthesis in Murine Atherosclerosis
Accumulation of hyaluronic acid (HA) is characteristic for atherosclerotic and restenotic lesions of patients with coronary heart disease. HA is synthesized by three HA-synthase (HAS) isoforms, HAS1, −2 and −3 and regulates migration and cell proliferation. Cyclooxygenase 2 (COX2) is expressed by vascular endothelium and is induced during human atherosclerosis in macrophages and smooth muscle cells (SMC). Colocalization of HA and COX2 occurs in human atherosclerosis and vein grafts stenosis. The aim of the present study was to investigate whether COX2-dependent prostaglandin synthesis is involved in the regulation of HA-synthesis during atherosclerosis. ApoE-deficient mice were treated with the COX2 specific inhibitor rofecoxib (50 mg/kg/day) and with the non selective COX inhibitor indomethacin (3 mg/kg/day) for 8 weeks beginning at the age of 15 weeks. Subsequently, animals were sacrificed and the aortic root analyzed with respect to plaque HA content. Total mRNA was isolated from the aorta and used for quantification of HAS-isoform mRNA expression. Urinary excretion of 2,3-dinor thromboxane B2 (2,3-dinorTXB2) was not affected by rofecoxib whereas indomethacin caused a nearly total suppression of 2,3-dinorTXB2 excretion. The main PGI2 metabolite 2,3-dinor-6-keto-PGF-1alpha showed 50% reduction in response to rofecoxib and complete reduction in response to indomethacin. Thus rofecoxib and indomethacin treatments were effective in selective inhibition of COX2 and inhibition of both COX1 and COX2 respectively. HAS1 mRNA expression in thoracic aorta was decreased by rofecoxib (58 3 11 % of control, mean 3 SEM, n = 10, p < 0.05) and indomethacin (63 ± 7 % of control, mean ± SEM, n = 12, p < 0.05). HAS2 and HAS3 showed a trend towards reduced mRNA expression in response to rofecoxib and indomethacin. Furthermore, in atherosclerotic plaques of the aortic root rofecoxib significantly inhibited HA-accumulation (77 ± 3 % of control, mean ± SEM, n = 10, p < 0.05) and indomethacin caused a trend towards reduced HA as determined by affinity histochemistry. Taken together pharmacologic inhibition of COX2-dependent prostaglandin synthesis causes inhibition HAS1 expression and HA-accumulation in atherosclerotic plaques in a murine model of atherosclerosis.