on October 28, 2004
Published online before print October 28, 2004, doi: 10.1161/01.ATV.0000148703.43429.25
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Submitted on July 24, 2004
Accepted on October 7, 2004
2-Chlorohexadecanal Derived From Hypochlorite-Modified High-Density Lipoprotein-Associated Plasmalogen Is a Natural Inhibitor of Endothelial Nitric Oxide Biosynthesis
Gunther Marsche ;
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.
* To whom correspondence should be addressed. 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/Ocl-)--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.
Key words: myeloperoxidase • 2-chlorinated fatty aldehyde • atherosclerosis • modified lipids • glomerulosclerosis • neutrophils
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