JBC272 - Communication Reactive Nitrogen Intermediates...

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Reactive Nitrogen Intermediates Promote Low Density Lipoprotein Oxidation in Human Atherosclerotic Intima* (Received for publication, September 13, 1996, and in revised form, November 12, 1996) Christiaan Leeuwenburgh‡, Medora M. Hardy§, Stanley L. Hazen‡ , Peter Wagner‡, Shuji Oh-ishi‡, Urs P. Steinbrecher i , and Jay W. Heinecke‡**‡‡ From the Departments of Medicine and of **Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, § Searle Research, Monsanto Company, St. Louis, Missouri 63167, and the i Department of Medicine, University of British Columbia, Vancouver, BC Canada V5Z 4E3 Oxidized low density lipoprotein (LDL) may be of cen- tral importance in triggering atherosclerosis. One po- tential pathway involves the production of nitric oxide (NO) by vascular wall endothelial cells and macro- phages. NO reacts with superoxide to form peroxynitrite (ONOO 2 ), a potent agent of LDL oxidation in vitro . ONOO 2 nitrates the aromatic ring of free tyrosine to produce 3-nitrotyrosine, a stable product. To explore the role of reactive nitrogen species such as ONOO 2 in the pathogenesis of vascular disease, we developed a highly sensitive and specific method involving gas chro- matography and mass spectrometry to quantify 3-nitro- tyrosine levels in proteins. In vitro studies demon- strated that 3-nitrotyrosine was a highly specific marker for LDL oxidized by ONOO 2 . LDL isolated from the plasma of healthy subjects had very low levels of 3-nitrotyrosine (9 6 7 m mol/mol of tyrosine). In striking contrast, LDL isolated from aortic atherosclerotic in- tima had 90-fold higher levels (840 6 140 m mol/mol of tyrosine). These observations strongly support the hy- pothesis that reactive nitrogen species such as ONOO 2 form in the human artery wall and provide direct evi- dence for a specific reaction pathway that promotes LDL oxidation in vivo . The detection of 3-nitrotyrosine in LDL isolated from vascular lesions raises the possi- bility that NO, by virtue of its ability to form reactive nitrogen intermediates, may promote atherogenesis, counteracting the well-established anti-atherogenic ef- fects of NO. An elevated level of low density lipoprotein (LDL) 1 is a major risk factor for premature atherosclerotic vascular disease. However, a wealth of evidence suggests that LDL must be oxidatively modified to damage the artery wall (1, 2). Pathways that oxidize lipid and protein may thus be pivotal to the devel- opment of atherosclerosis. LDL oxidation has been widely stud- ied in vitro , but the mechanisms that promote oxidation within the artery wall remain poorly understood (2). We have described one potential pathway for LDL oxidation that involves oxidants generated by myeloperoxidase, an en- zyme secreted by phagocytes (3). Another pathway involves nitrogen monoxide (nitric oxide; NO) generated by vascular wall cells (4). NO is a relatively stable free radical that fails to oxidize LDL at physiological pH (5). However, NO reacts rap- idly with superoxide to form peroxynitrite (ONOO 2 ; Ref. 6), a
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