Protein carbamylation links inflammation, smoking, uremia and atherogenesis

被引:596
作者
Wang, Zeneng
Nicholls, Stephen J.
Rodriguez, E. Rene
Kummu, Outi
Horkko, Sohvi
Barnard, John
Reynolds, Wanda F.
Topol, Eric J.
DiDonato, Joseph A.
Hazen, Stanley L.
机构
[1] Cleveland Clin Fdn, Dept Cell Biol, Cleveland, OH 44195 USA
[2] Cleveland Clin Fdn, Dept Cardiovasc Med, Cleveland, OH 44195 USA
[3] Cleveland Clin Fdn, Dept Pathol, Cleveland, OH 44195 USA
[4] Univ Oulu, Dept Internal Med, Oulu, Finland
[5] Univ Oulu, Bioctr Oulu, Oulu, Finland
[6] Oulu Univ Hosp, Clin Res Ctr, Oulu, Finland
[7] Cleveland Clin Fdn, Dept Quantitat Hlth Sci, Cleveland, OH 44195 USA
[8] Sidney Kimmel Canc Ctr, San Diego, CA 92121 USA
关键词
D O I
10.1038/nm1637
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 [生物化学与分子生物学]; 081704 [应用化学];
摘要
Post- translational modification and functional impairment of proteins through carbamylation is thought to promote vascular dysfunction during end- stage renal disease. Cyanate, a reactive species in equilibrium with urea, carbamylates protein lysine residues to form epsilon-carbamyllysine (homocitrulline), altering protein structure and function. We now report the discovery of an alternative and quantitatively dominant mechanism for cyanate formation and protein carbamylation at sites of inflammation and atherosclerotic plaque: myeloperoxidase-catalyzed oxidation of thiocyanate, an anion abundant in blood whose levels are elevated in smokers. We also show that myeloperoxidase-catalyzed lipoprotein carbamylation facilitates multiple pro- atherosclerotic activities, including conversion of low-density lipoprotein into a ligand for macrophage scavenger receptor A1 recognition, cholesterol accumulation and foam-cell formation. In two separate clinical studies ( combined n = 1,000 subjects), plasma levels of protein-bound homocitrulline independently predicted increased risk of coronary artery disease, future myocardial infarction, stroke and death. We propose that protein carbamylation is a mechanism linking inflammation, smoking, uremia and coronary artery disease pathogenesis.
引用
收藏
页码:1176 / 1184
页数:9
相关论文
共 47 条
[1]
Nitric oxide is a physiological substrate for mammalian peroxidases [J].
Abu-Soud, HM ;
Hazen, SL .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (48) :37524-37532
[2]
CARDIOVASCULAR-DISEASE RISK PROFILES [J].
ANDERSON, KM ;
ODELL, PM ;
WILSON, PWF ;
KANNEL, WB .
AMERICAN HEART JOURNAL, 1991, 121 (01) :293-298
[3]
Eosinophil peroxidase oxidation of thiocyanate - Characterization of major reaction products and a potential sulfhydryl-targeted cytotoxicity system [J].
Arlandson, M ;
Decker, T ;
Roongta, VA ;
Bonilla, L ;
Mayo, KH ;
MacPherson, JC ;
Hazen, SL ;
Slungaard, A .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (01) :215-224
[4]
Myeloperoxidase polymorphism related to cardiovascular events in coronary artery disease [J].
Asselbergs, FW ;
Reynolds, WF ;
Cohen-Tervaert, JW ;
Jessurun, GAJ .
AMERICAN JOURNAL OF MEDICINE, 2004, 116 (06) :429-430
[5]
Myeloperoxidase enhances nitric oxide catabolism during myocardial ischemia and reperfusion [J].
Baldus, S ;
Heitzer, T ;
Eiserich, JP ;
Lau, D ;
Mollnau, H ;
Ortak, M ;
Petri, S ;
Goldmann, B ;
Duchstein, HJ ;
Berger, J ;
Helmchen, U ;
Freeman, BA ;
Meinertz, T ;
Münzel, T .
FREE RADICAL BIOLOGY AND MEDICINE, 2004, 37 (06) :902-911
[6]
GEL ISOELECTRIC FOCUSING FOR FOLLOWING SUCCESSIVE CARBAMYLATIONS OF AMINO GROUPS IN CHYMOTRYPSINOGEN-A [J].
BOBB, D ;
HOFSTEE, BHJ .
ANALYTICAL BIOCHEMISTRY, 1971, 40 (01) :209-+
[7]
Prognostic value of myeloperoxidase in patients with chest pain [J].
Brennan, M ;
Penn, MS ;
Van Lente, F ;
Nambi, V ;
Shishehbor, MH ;
Aviles, RJ ;
Goormastic, M ;
Pepoy, ML ;
McErlean, ES ;
Topol, EJ ;
Nissen, SE ;
Hazen, SL .
NEW ENGLAND JOURNAL OF MEDICINE, 2003, 349 (17) :1595-1604
[8]
A tale of two controversies -: Defining both the role of peroxidases in nitrotyrosine formation in vivo using eosinophil peroxidase and myeloperoxidase-deficient mice, and the nature of peroxidase-generated reactive nitrogen species [J].
Brennan, ML ;
Wu, WJ ;
Fu, XM ;
Shen, ZZ ;
Song, W ;
Frost, H ;
Vadseth, C ;
Narine, L ;
Lenkiewicz, E ;
Borchers, MT ;
Lusis, AJ ;
Lee, JJ ;
Lee, NA ;
Abu-Soud, HM ;
Ischiropoulos, H ;
Hazen, SL .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (20) :17415-17427
[9]
Transgenic mice express human MPO-463G/A alleles at atherosclerotic lesions, developing hyperlipidemia and obesity in-463G males [J].
Castellani, Lawrence W. ;
Chang, James J. ;
Wang, Xuping ;
Lusis, Aldons J. ;
Reynolds, Wanda F. .
JOURNAL OF LIPID RESEARCH, 2006, 47 (07) :1366-1377
[10]
Myeloperoxidase, a leukocyte-derived vascular NO oxidase [J].
Eiserich, JP ;
Baldus, S ;
Brennan, ML ;
Ma, WX ;
Zhang, CX ;
Tousson, A ;
Castro, L ;
Lusis, AJ ;
Nauseef, WM ;
White, CR ;
Freeman, BA .
SCIENCE, 2002, 296 (5577) :2391-2394