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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:2302.)
© 2004 American Heart Association, Inc.

Vascular Biology

2-Chlorohexadecanal Derived From Hypochlorite-Modified High-Density Lipoprotein–Associated Plasmalogen Is a Natural Inhibitor of Endothelial Nitric Oxide Biosynthesis

Gunther Marsche; Regine Heller; Günter Fauler; Alenka Kovacevic; Alexander Nuszkowski; Wolfgang Graier; Wolfgang Sattler; Ernst Malle

From the Institute of Molecular Biology and Biochemistry (G.M., A.K., W.G., W.S., E.M.) and the Clinical Institute of Medical and Chemical Laboratory Diagnostics (G.F.), Medical University Graz, Austria; and the Institute of Molecular Cell Biology (R.H., A.N.), University of Jena, Erfurt, Germany.

Correspondence to Dr Ernst Malle, Medical University Graz, Institute of Molecular Biology and Biochemistry, A-8010 Graz, Austria. E-mail ernst.malle{at}meduni-graz.at

Objective— Myeloperoxidase, a heme enzyme that is present and active in human atherosclerotic lesions, provides a source for the generation of proinflammatory chlorinated reactants contributing to endothelial dysfunction. Modification of high-density lipoprotein (HDL) by hypochlorous acid/hypochlorite (HOCl/Oce^–)—generated in vivo by the myeloperoxidase-hydrogen peroxide-chloride system of activated phagocytes—forms a proatherogenic lipoprotein particle that binds to and is internalized by endothelial cells.

Methods and Results— Here we show that HDL, modified with physiologically relevant HOCl concentrations, attenuates the expression and activity of vasculoprotective endothelial nitric oxide synthase. HOCl-HDL promotes dislocalization of endothelial nitric oxide synthase from the plasma membrane and perinuclear location of human umbilical venous endothelial cells. We could identify 2-chlorohexadecanal as the active component mediating this inhibitory activity. This chlorinated fatty aldehyde is formed during HOCl-mediated oxidative cleavage of HDL-associated plasmalogen.

Conclusion— 2-Chlorohexadecanal, produced by the myeloperoxidase-hydrogen peroxide-chloride system of activated phagocytes may act as a mediator of vascular injury associated with ischemia-reperfusion injury, glomerulosclerosis, and atherosclerosis.

Modification of HDL by HOCl (generated in vivo by the myeloperoxidase–H₂O₂ system) promotes dislocalization of eNOS from the plasma membrane and perinuclear location of endothelial cells, and attenuates eNOS expression and NO biosynthesis. The component mediating this proatherogenic effect was identified as 2-chlorohexadecanal formed during HOCl-mediated attack of lipoprotein-associated plasmalogen.

Key Words: myeloperoxidase • 2-chlorinated fatty aldehyde • atherosclerosis • modified lipids • glomerulosclerosis • neutrophils

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