The 15-lipoxygenase-modified high density lipoproteins 3 fail to inhibit the TNF-alpha-induced inflammatory response in human endothelial cells.
Endothelial dysfunction represents one of the earliest events in vascular atherogenesis. Proinflammatory stimuli activate endothelial cells, resulting in an increased expression of adhesion molecules and chemoattractants that mediate leukocyte and monocyte adhesion, migration, and homing. High density lipoproteins (HDL) inhibit endothelial cell expression of adhesion molecules in response to proinflammatory stimuli. In the present work, we demonstrate that the modification of HDL(3) (the major and the most antiatherogenic HDL subfraction) by 15-lipoxygenase (15-LO), an enzyme overexpressed in the atherosclerotic lesions, impairs the anti-inflammatory activity of this lipoprotein. The 15-LO-modified HDL(3) failed to inhibit TNF-alpha-mediated mRNA and protein induction of adhesion molecules and MCP-1 in several models of human endothelial cells, and promoted inflammatory response by up-regulating the expression of such mediators of inflammation and by increasing monocyte adhesion to endothelial cells. Moreover, 15-LO-modified HDL(3) were unable to contrast the formation of reactive oxygen species in cells incubated with TNF-alpha, and increased the reactive oxygen species content in unstimulated cells. Activation of NF-kappaB and AP-1 was mainly involved in the expression of adhesion molecules and MCP-1 induced by 15-LO-HDL(3). Altogether, these results demonstrate that enzymatic modification induced by 15-LO impaired the protective role of HDL(3), generating a dysfunctional lipoprotein endowed with proinflammatory characteristics.
Pirillo
Angela
A
Department of Pharmacological Sciences, University of Milan, Milan, Italy. angela.pirillo@unimi.it
Uboldi
Patrizia
P
Bolego
Chiara
C
Kuhn
Hartmut
H
Catapano
Alberico Luigi
AL
D001093:Arachidonate 15-Lipoxygenase / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D002460:Cell Line; D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D004730:Endothelium, Vascular / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D053440:Lipoproteins, HDL3 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D008833:Microcirculation / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*; D020298:U937 Cells
D015815:Cell Adhesion Molecules; D018836:Inflammation Mediators; D053440:Lipoproteins, HDL3; D014409:Tumor Necrosis Factor-alpha; C515716:ALOX15 protein, human; D001093:Arachidonate 15-Lipoxygenase