COX-2 expression in atherosclerosis: the good, the bad or the ugly?

Cyclooxygenase (COX) is the rate limiting enzyme catalyzing the conversion of arachidonic acid into prostanoids, lipid mediators critically implicated in a variety of physiological and pathophysiological processes, including inflammation, vascular and renal homeostasis, and immune responses. Since the early 1990s it has been appreciated that two isoforms of COX exist, referred to as COX-1 and COX-2. Although structurally homologous, COX-1 and COX-2 are regulated by two independent and quite different systems and have different functional roles. In the setting of acute ischemic syndromes it has been recognized that COX pathway plays an important role; however, whereas the function of platelet COX-1 in acute ischemic diseases is firmly established, the role of COX-2 in atherothrombosis remains controversial. The complex role of COX-2 in this setting is also confirmed by the unexpected cardiovascular side effects of long-term treatment with COX-2 inhibitors. In this article, we review the pattern of expression of COX-2 in the cellular players of atherothrombosis, its role as a determinant of plaque vulnerability, the effects of the variable expression of upstream and downstream enzymes in the prostanoid biosynthesis on COX-2 expression and inhibition.

Relationship between reduced BCL-2 expression in circulating mononuclear cells and early nephropathy in type 1 diabetes.

Microalbuminuria is the earliest clinical evidence of diabetic nephropathy, but the mechanisms linking hyperglycemia and kidney complications are not clear. The aim of this study was to evaluate whether enhanced oxidative stress in patients with microalbuminuria can contribute to diabetic nephropathy development through downregulation of the antiapoptotic gene Bcl-2 that promotes in turn a pro-inflammatory status. We studied 30 patients with type 1 diabetes (15 with and 15 without microalbuminuria) compared to 15 matched healthy controls. Plasma oxidant status, and expression of Bcl-2, activated NF-kB, inducible Nitric Oxide synthase (iNOS), and monocyte chemoattractant protein (MCP)-1 in circulating monocytes were evaluated at baseline and after 8-week oral vitamin E treatment (600 mg b.i.d.). Bcl-2 expression was significantly reduced in microalbuminuric diabetic patients as a consequence of increased oxidant burden secondary to persistent hyperglycemia. Bcl-2 down-regulation was associated with enhanced expression of NF-kB, iNOS and MCP-1, and showed a strong correlation with the albumin excretion rate. Low Bcl-2 expression and high inflammatory status were normalized by vitamin E both in vivo and in vitro. Our study showed that Bcl-2 down-regulation in diabetic patients with poor glycemic control results in the activation of the NF-kB pathway leading to the development of nephropathy. Vitamin E might provide a novel form of therapy for prevention of nephropathy in diabetic patients in which an acceptable glycemic control is difficult to achieve despite insulin therapy.