Augmented Expression of Cyclooxygenase-2 in Human Atherosclerotic Lesions

Abstract

Cyclooxygenase-1 (Cox-1) and Cox-2 convert arachidonic acid to prostaglandin H(2), the precursor of other prostaglandins and thromboxanes, eicosanoids important in vascular pathophysiology. However, knowledge of the expression of cyclooxygenases within atherosclerotic lesions is scant. This study tested the hypothesis that human atheroma and nonatherosclerotic arteries express the two Cox isoforms differentially. Cox-1 mRNA and protein localized on endothelial and medial smooth muscle cells of normal arteries (n = 5), whereas Cox-2 expression was not detectable. In contrast, atheromatous (n = 7) lesions contained both Cox-1 and Cox-2, colocalizing mainly with macrophages of the shoulder region and lipid core periphery, whereas smooth muscle cells showed lower levels, as demonstrated by immunohistochemical and in situ hybridization analysis. Furthermore, microvascular endothelium in plaques showed notable staining for both isoforms. In accord with immunohistochemical studies, Western blot analysis of protein extracts from normal arteries revealed constitutive Cox-1, but not Cox-2, expression. Extracts of atheromatous lesions, however, contained both Cox-1 and Cox-2 protein, detected as two immunoreactive proteins of approximately 70 and 50 kd. Macrophages expressed the short form of Cox-1/-2 constitutively after several days of in vitro culture, rather than the 70-kd protein. These results shed new light on the inflammatory pathways that operate in human atheroma. In particular, the expression of Cox-2 in atheromatous, but not in unaffected, arteries has therapeutic implications, given the advent of selective Cox-2 inhibitors.

γ-Tocopherol and its major metabolite, in contrast to α-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells

“…In addition, inflammation plays a key role in the initiation and development of atherosclerosis and augmented expression of COX-2 has been found in human atherosclerotic lesions but not in normal arteries (52). The anti-inflammatory properties of ␥T may be important in preventing cardiovascular disease.…”

Cyclooxygenase- and lipoxygenase-dependent relaxation to arachidonic acid in rabbit small mesenteric arteries

“…These findings confirm that both isoforms of COX are present, functional, and involved in relaxation responses to AA. The expression of COX-2 in normal mesenteric arteries was unexpected, given that this isoform is predominantly expressed in disease states such as inflammation and atherosclerosis (1,6,10,31). However, a previous study (12) has reported that both COX-1 and -2 are constitutively expressed in the rat lung vasculature and that COX-2 plays a predominant role in prostanoid-related regulation of pulmonary vascular tone.…”

Extracellular Matrix-induced Cyclooxygenase-2 Regulates Macrophage Proteinase Expression

“…Macrophage proteinase expression contributes to the rupture of atherosclerotic plaques, which leads to thrombosis, myocardial infarction, and stroke. Several studies (67)(68)(69) have demonstrated increased COX-2 expression in atherosclerotic lesions. Moreover, COX-2, prostaglandin E synthase, and MMP activities were elevated on the shoulders of symptomatic plaques (70).…”