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The 15-Lipoxygenase-Modified High Density Lipoproteins 3 Fail to Inhibit the TNF--Induced Inflammatory Response in Human Endothelial Cells¹

Angela Pirillo^2,*, Patrizia Uboldi^*, Chiara Bolego, Hartmut Kuhn and Alberico Luigi Catapano^*

^* Department of Pharmacological Sciences, University of Milan, Milan, Italy; Department of Pharmacology and Anesthesiology, University of Padua, Padua, Italy; and Institute of Biochemistry, University Medicine Berlin–Charité, Berlin, Germany

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 HDL₃ (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 HDL₃ failed to inhibit TNF--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 HDL₃ were unable to contrast the formation of reactive oxygen species in cells incubated with TNF-, and increased the reactive oxygen species content in unstimulated cells. Activation of NF-B and AP-1 was mainly involved in the expression of adhesion molecules and MCP-1 induced by 15-LO-HDL₃. Altogether, these results demonstrate that enzymatic modification induced by 15-LO impaired the protective role of HDL₃, generating a dysfunctional lipoprotein endowed with proinflammatory characteristics.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from Università degli Studi di Milano (Fondo per gli Investimenti e la Ricerca Scientifica e Tecnologica) and Istituto Nazionale per le Ricerche Cardiovascolari.

² Address correspondence and reprint requests to Dr. Angela Pirillo, Department of Pharmacological Sciences, Via Balzaretti, 9, 20133 Milano, Italy. E-mail address: angela.pirillo{at}unimi.it

³ Abbreviations used in this paper: HDL, high density lipoprotein; 15-LO, 15-lipoxygenase; BCECF-AM, 2,7-bis(2-carboxyethyl)-5(6)-carboxyfluorescein acetoxymethylester; DCFH-DA, 2,7-dichlorofluorescein diacetate; h15-LO, human 15-LO; HAEC, human aortic endothelial cell; HMEC, human microvascular endothelial cell; LDL, low density lipoprotein; LPA, lysophosphatidic acid; LPC, lysophosphatidylcholine; ROS, reactive oxygen species; S1P, sphingosine-1-phosphate; SR-BI, scavenger receptor class B type I.