Selective nitration of prostacyclin synthase and defective vasorelaxation in atherosclerotic bovine coronary arteries

被引:141
作者
Zou, MH
Leist, M
Ullrich, V
机构
[1] Univ Konstanz, Fac Biol, Dept Biol Chem, D-78457 Constance, Germany
[2] Univ Konstanz, Fac Biol, Dept Mol Toxicol, D-78457 Constance, Germany
关键词
D O I
10.1016/S0002-9440(10)65390-4
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
Prostacyclin synthase (PCS) is an enzyme with antithrombotic, antiproliferative, and dilatory functions in the normal vasculature, and inactivation of PCS by tyrosine nitration may favor atherosclerotic processes. Here, we show that PCS is nitrated and inactivated in early stage atherosclerotic lesions (focal intimal thickenings). Immunoprecipitation with antibodies raised against nitrotyrosine yielded PCS as the main nitrated protein in blood vessels. Moreover, we identified two nitrated degradation products of PCS with molecular mass of 30 and 46 kd, which were selective for atherosclerotic tissue. Agonist (acetylcholine, angiotensin II)-induced prostacyclin formation was decreased in atherosclerotic vessels compared with normal tissue, whereas PGE(2) formation was increased and cyclooxygenase activity remained unchanged. A selective loss of PCS activity was confirmed by direct measurement of enzymatic activity. In line with this, we observed defective relaxation of early atherosclerotic vessels following vasoconstrictive stimulation, This functional impairment was completely reversed by coincubation with an antagonist of the thromboxane/PGH(2) receptor but not by a thromboxane synthase inhibitor. These data suggest that reduced PCS activity in atherosclerotic arteries prevents the rapid use of PGH(2), which accumulates and acts as an agonist on the vasoconstrictive thromboxane receptor.
引用
收藏
页码:1359 / 1365
页数:7
相关论文
共 20 条
[1]   EXTENSIVE NITRATION OF PROTEIN TYROSINES IN HUMAN ATHEROSCLEROSIS DETECTED BY IMMUNOHISTOCHEMISTRY [J].
BECKMANN, JS ;
YE, YZ ;
ANDERSON, PG ;
CHEN, J ;
ACCAVITTI, MA ;
TARPEY, MM ;
WHITE, CR ;
BECKMAN, JS .
BIOLOGICAL CHEMISTRY HOPPE-SEYLER, 1994, 375 (02) :81-88
[2]  
Buttery LDK, 1996, LAB INVEST, V75, P77
[3]   Formation of nitric oxide derived inflammatory oxidants by myeloperoxidase in neutrophils [J].
Eiserich, JP ;
Hristova, M ;
Cross, CE ;
Jones, AD ;
Freeman, BA ;
Halliwell, B ;
van der Vliet, A .
NATURE, 1998, 391 (6665) :393-397
[4]  
HARLOW E, 1988, ANTIBODIES LABORATOR, P653
[5]   Aspirin improves endothelial dysfunction in atherosclerosis [J].
Husain, S ;
Andrews, NP ;
Mulcahy, D ;
Panza, JA ;
Quyyumi, AA .
CIRCULATION, 1998, 97 (08) :716-720
[6]   IMPAIRED ACETYLCHOLINE-MEDIATED VASODILATION IN PATIENTS WITH CONGESTIVE-HEART-FAILURE - ROLE OF ENDOTHELIUM-DERIVED VASODILATING AND VASOCONSTRICTING FACTORS [J].
KATZ, SD ;
SCHWARZ, M ;
YUEN, J ;
LEJEMTEL, TH .
CIRCULATION, 1993, 88 (01) :55-61
[7]   IMPAIRED ENDOTHELIUM-MEDIATED VASODILATION IN THE PERIPHERAL VASCULATURE OF PATIENTS WITH CONGESTIVE-HEART-FAILURE [J].
KATZ, SD ;
BIASUCCI, L ;
SABBA, C ;
STROM, JA ;
JONDEAU, G ;
GALVAO, M ;
SOLOMON, S ;
NIKOLIC, SD ;
FORMAN, R ;
LEJEMTEL, TH .
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 1992, 19 (05) :918-925
[8]   SELECTIVE-INHIBITION OF CYCLOOXYGENASE-2 [J].
KLEIN, T ;
NUSING, RM ;
PFEILSCHIFTER, J ;
ULLRICH, V .
BIOCHEMICAL PHARMACOLOGY, 1994, 48 (08) :1605-1610
[9]   Reactive nitrogen intermediates promote low density lipoprotein oxidation in human atherosclerotic intima [J].
Leeuwenburgh, C ;
Hardy, MM ;
Hazen, SL ;
Wagner, P ;
Ohishi, S ;
Steinbrecher, UP ;
Heinecke, JW .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (03) :1433-1436
[10]   PARADOXICAL VASOCONSTRICTION INDUCED BY ACETYLCHOLINE IN ATHEROSCLEROTIC CORONARY-ARTERIES [J].
LUDMER, PL ;
SELWYN, AP ;
SHOOK, TL ;
WAYNE, RR ;
MUDGE, GH ;
ALEXANDER, RW ;
GANZ, P .
NEW ENGLAND JOURNAL OF MEDICINE, 1986, 315 (17) :1046-1051