Histamine upregulates gene expression of endothelial nitric oxide synthase in human vascular endothelial cells

被引:76
作者
Li, HG
Burkhardt, C
Heinrich, UR
Brausch, I
Xia, N
Förstermann, U
机构
[1] Univ Mainz, Dept Pharmacol, D-55131 Mainz, Germany
[2] Univ Mainz, Dept Otorhinolaryngol, D-55131 Mainz, Germany
[3] Univ Heidelberg, Dept Cardiol, D-6900 Heidelberg, Germany
[4] Huazhong Univ Sci & Technol, Tongji Med Coll, Dept Pathophysiol, Wuhan 430074, Peoples R China
关键词
endothelium-derived factors; signal transduction; oxidative stress; atherosclerosis; coronary disease;
D O I
10.1161/01.CIR.0000066697.19571.AF
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background-Histamine has a short-term, transient, stimulating effect on endothelial nitric oxide synthase (eNOS) activity; however, long-term effects on eNOS have not been described yet. In addition, the vascular effect of histamine seems to depend critically on eNOS functionality. Therefore, we studied the effects of histamine on eNOS gene expression and function. Methods and Results-In human umbilical vein endothelial cells (HUVECs) and HUVEC-derived EA.hy 926 cells, histamine upregulated eNOS mRNA (RNase protection assay) and protein (electron microscopic immunocytochemistry) expression. The upregulation of eNOS could be prevented by mepyramine, a selective antagonist at the H-1 receptor, but not by H-2 and H-3 receptor antagonists. Incubation of EA.hy 926 cells with histamine led to the activation of calcium/calmodulin-dependent protein kinase II (CaMK II; in vitro phosphorylation assay). The histamine-induced eNOS expression was completely prevented by KN-93, an inhibitor of CaMK II. Histamine increased the activity of a 1.6-kb human eNOS promoter fragment (luciferase reporter gene assay), an effect that was also blocked by mepyramine. Under normal conditions, eNOS upregulation by histamine resulted in increased nitric oxide production (measured by nitric oxide chemiluminescence and RFL-6 reporter cell assay). Under conditions of oxidative stress, however, the eNOS upregulated by histamine produced reactive oxygen species (CM-H(2)DCFDA oxidation-based fluorescence assay). Conclusions-Stimulation of the H-1 receptor increases eNOS transcription in endothelial cells by a signaling pathway involving CaMK II. This eNOS upregulation may be protective under normal conditions, but it may become harmful under conditions of oxidative stress when eNOS produces reactive oxygen species at the expense of nitric oxide.
引用
收藏
页码:2348 / 2354
页数:7
相关论文
共 31 条
[1]   ROLE OF H1 RECEPTORS AND P-SELECTIN IN HISTAMINE-INDUCED LEUKOCYTE ROLLING AND ADHESION IN POSTCAPILLARY VENULES [J].
ASAKO, H ;
KUROSE, I ;
WOLF, R ;
DEFREES, S ;
ZHENG, ZL ;
PHILLIPS, ML ;
PAULSON, JC ;
GRANGER, DN .
JOURNAL OF CLINICAL INVESTIGATION, 1994, 93 (04) :1508-1515
[2]   EFFECT OF PLATELET FACTORS ON MIGRATION OF CULTURED BOVINE AORTIC ENDOTHELIAL AND SMOOTH-MUSCLE CELLS [J].
BELL, L ;
MADRI, JA .
CIRCULATION RESEARCH, 1989, 65 (04) :1057-1065
[3]   Induction of endothelial NO synthase by hydrogen peroxide via a Ca2+/calmodulin-dependent protein kinase II/janus kinase 2-dependent pathway [J].
Cai, H ;
Davis, ME ;
Drummond, GR ;
Harrison, DG .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2001, 21 (10) :1571-1576
[4]   Heterogeneity of expression of E- and P-selectins in vivo [J].
Eppihimer, MJ ;
Wolitzky, B ;
Anderson, DC ;
Labow, MA ;
Granger, DN .
CIRCULATION RESEARCH, 1996, 79 (03) :560-569
[5]   Phosphorylation of Thr495 regulates Ca2+/calmodulin-dependent endothelial nitric oxide synthase activity [J].
Fleming, I ;
Fisslthaler, B ;
Dimmeler, S ;
Kemp, BE ;
Busse, R .
CIRCULATION RESEARCH, 2001, 88 (11) :E68-E75
[6]   INCREASED ADVENTITIAL MAST-CELLS IN A PATIENT WITH CORONARY SPASM [J].
FORMAN, MB ;
OATES, JA ;
ROBERTSON, D ;
ROBERTSON, RM ;
ROBERTS, LJ ;
VIRMANI, R .
NEW ENGLAND JOURNAL OF MEDICINE, 1985, 313 (18) :1138-1141
[7]   QUANTITATIVE PHARMACOLOGIC RESPONSES OF NORMAL AND ATHEROSCLEROTIC ISOLATED HUMAN EPICARDIAL CORONARY-ARTERIES [J].
GINSBURG, R ;
BRISTOW, MR ;
DAVIS, K ;
DIBIASE, A ;
BILLINGHAM, ME .
CIRCULATION, 1984, 69 (02) :430-440
[8]   Immuno-electron microscopic localization of the α1 and β1-subunits of soluble guanylyl cyclase in the guinea pig organ of Corti [J].
Heinrich, UR ;
Maurer, J ;
Koesling, D ;
Mann, W ;
Förstermann, U .
BRAIN RESEARCH, 2000, 885 (01) :6-13
[9]   Effects of histamine and interleukin-4 synthesized in arterial intima on phagocytosis by monocytes/macrophages in relation to atherosclerosis [J].
Higuchi, S ;
Tanimoto, A ;
Arima, N ;
Xu, H ;
Murata, Y ;
Hamada, T ;
Makishima, K ;
Sasaguri, Y .
FEBS LETTERS, 2001, 505 (02) :217-222
[10]  
Hink U, 2001, CIRC RES, V88, pE14