Lipid Inflammatory Mediators in Diabetic Vascular Disease

Abstract

Abstract-Type 2 diabetes is associated with significantly accelerated rates of macrovascular complications such as atherosclerosis. Emerging evidence now indicates that atherosclerosis is an inflammatory disease and that certain inflammatory markers may be key predictors of diabetic atherosclerosis. Proinflammatory cytokines and cellular adhesion molecules expressed by vascular and blood cells during stimulation by growth factors and cytokines seem to play major roles in the pathophysiology of atherosclerosis and diabetic vascular complications. However, more recently, data suggest that inflammatory responses can also be elicited by smaller oxidized lipids that are components of atherogenic oxidized low-density lipoprotein or products of phospholipase activation and arachidonic acid metabolism. These include oxidized lipids of the lipoxygenase and cyclooxygenase pathways of arachidonic acid and linoleic acid metabolism. These lipids have potent growth, vasoactive, chemotactic, oxidative, and proinflammatory properties in vascular smooth muscle cells, endothelial cells, and monocytes. Cellular and animal models indicate that these enzymes are induced under diabetic conditions, have proatherogenic effects, and also mediate the actions of growth factors and cytokines. This review highlights the roles of the inflammatory cyclooxygenase and 12/15-lipoxygenase pathways in the pathogenesis of diabetic vascular disease. Key Words: lipoxygenase Ⅲ diabetes Ⅲ diabetes complications Ⅲ inflammation Ⅲ lipids D iabetes is associated with significantly accelerated rates of cardiovascular complications such as atherosclerosis and hypertension. In particular, type 2 diabetes is associated with 2-to 4-fold increase in coronary artery disease. 1 This has been attributed to the clustering of several risk factors, including insulin resistance, hypertension, obesity, and dyslipidemia. 2,3 Multiple mechanisms contribute to vascular and arterial disease in the diabetic population. 2 Basic biochemical mechanisms have been described by which hyperglycemiainduced oxidant stress activates several downstream signals that mediate diabetic complications. 4 -8 Furthermore, advanced glycation end products formed by glucose-induced modification of proteins can act via their receptors such as RAGE and induce cellular oxidant stress, inflammation, and vascular dysfunction in diabetes. 9 -12 Recent evidence from laboratory and clinical studies demonstrates that diabetic atherosclerosis is not simply a disease of hyperlipidemia but also an inflammatory disorder involving multiple mediators such as C-reactive protein, cytokines such as tumor necrosis factor alpha, and interluekin-6 (IL-6). 2,13,14 A recent gene profiling study showed that high glucose treatment of monocytes leads to increased expression of multiple inflammatory cytokines, chemokines, and related factors, many of which are regulated by the proinflammatory transcription factor, nuclear factor-kappa B (NF-B). 15 The recognition now that highly effective antidiabetic agents, such as thi...

Mechanisms by which diabetes increases cardiovascular disease

“…Different molecular mechanisms associated with hyperglycemia have been identified including 1. increased glucose flux through the polyol pathway [5], 2. formation of advanced glycation end products (AGE) [5], (3) activation of protein kinase C (PKC) [5,6], 4. increased glucose flux through the hexosamine pathway [5], and activation of the 12/15-lipoxygenase (12/15-LO) pathway [7,8]. All these mechanisms finally lead to increased superoxide formation [5] (Figure 1).…”

“…Intracellular hyperglycemia induces PKC activity via increased levels of diacylglycerol (DAG) resulting mainly from DAG de novo synthesis [5,6]. Indirect PKC activation may be due to RAGE engagement or polyol pathway activation [5,6] or activation of 12/15-LO [7,8]. Various effects of PKC activation have been described which may promote atherogenesis.…”

“…12-and 15-lipoxygenase are enzymes that insert oxygen at the 12 or 15 carbon position into arachidonic acid leading to formation of 12(S)-and 15(S)-hydroxyeicosatetraeonic acid [8]. 12/15-LO is expressed in endothelial cells, smooth muscle cells, monocytes and macrophages, its acitivity has been shown to be increased by hyperglycemia [8].…”

“…12/15-LO is expressed in endothelial cells, smooth muscle cells, monocytes and macrophages, its acitivity has been shown to be increased by hyperglycemia [8]. 12/15-LO-deficient mice crossbred with either ApoE −/− or LDLR −/− mice displayed decreased atherosclerotic lesion size [34,35].…”

“…12/15-LO promotes oxidation of native to more atherogenic oxidized LDL [8]. Reduced IL-12 secretion upon stimulation with LPS suggests a role in the inflammatory response [8].…”