Published Online
on November 24, 2003

A more recent version of this article appeared on December 23, 2003

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Submitted on November 20, 2002
Revised on August 18, 2003
Accepted on August 18, 2003

Identification of -Chloro Fatty Aldehydes and Unsaturated Lysophosphatidylcholine Molecular Species in Human Atherosclerotic Lesions

Arun K. Thukkani BSc, Jane McHowat PhD, Fong-Fu Hsu PhD, Marie-Luise Brennan PhD, Stanley L. Hazen MD, PhD, and David A. Ford PhD^*

From the Department of Biochemistry and Molecular Biology (A.K.T., D.A.F.) and Pathology (J.M.), St Louis University Health Sciences Center, St Louis, Mo; Department of Medicine (F.-F.H.), Washington University, St Louis, Mo; and Departments of Cell Biology and Cardiovascular Medicine and Center for Cardiovascular Diagnostics and Prevention (M.-L.B., S.L.H.), Cleveland Clinic Foundation, Cleveland, Ohio.

^* To whom correspondence should be addressed. E-mail: fordda{at}slu.edu.

Background--A role for myeloperoxidase (MPO) as a mediator of coronary artery disease and acute coronary syndromes has recently received considerable attention. Although active MPO and hypochlorite-modified proteins and peptides have been detected in human atherosclerotic lesions, detection of novel chlorinated oxidized lipid species with proatherogenic properties in vivo has not yet been reported. In this study we show that MPO-generated reactive chlorinating species promote selective oxidative cleavage of plasmalogens, liberating -chloro fatty aldehydes and unsaturated lysophosphatidylcholine in human atherosclerotic lesions.

Methods and Results--Stable isotope dilution gas chromatography-mass spectrometry methods were used to identify and quantitate the -chloro fatty aldehyde, 2-chlorohexadecanal, in atherosclerotic versus normal human aorta. Compared with normal aorta, 2-chlorohexadecanal levels were elevated more than 1400-fold in atherosclerotic tissues. Parallel electrospray ionization mass spectrometry studies confirmed 34- and 20-fold increases in the plasmalogen cooxidation products, unsaturated lysophosphatidylcholine molecular species containing linoleic and arachidonic acid, respectively, within atherosclerotic compared with normal aorta. Unsaturated lysophosphatidylcholine containing docosahexaenoic acid was also detected in atherosclerotic but not in normal aorta. Exposure of primary human coronary artery endothelial cells to plasmalogen-derived lysophosphatidylcholine molecular species produced marked increases in P-selectin surface expression.

Conclusions--The present studies demonstrate that plasmalogens are attacked by MPO-derived reactive chlorinating species within human atheroma. The resultant species formed, -chloro fatty aldehydes and unsaturated lysophospholipids, possess proatherogenic properties, as shown by induction of P-selectin surface expression in primary human coronary artery endothelial cells.

Key words: coronary disease • aorta • atherosclerosis

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