Vascular incorporation of alpha-tocopherol prevents endothelial dysfunction due to oxidized LDL by inhibiting protein kinase C stimulation

被引:178
作者
Keaney, JF [1 ]
Guo, Y [1 ]
Cunningham, D [1 ]
Shwaery, GT [1 ]
Xu, AM [1 ]
Vita, JA [1 ]
机构
[1] BOSTON UNIV,MED CTR,EVANS MEM DEPT MED,BOSTON,MA 02118
关键词
endothelium; nitric oxide; vitamin E; antioxidants; lipoproteins;
D O I
10.1172/JCI118804
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Excess vascular oxidative stress has been linked to impaired endothelium-dependent arterial relaxation in hypercholesterolemia, alpha-Tocopherol (AT) preserves endothelial function in hypercholesterolemia although the mechanism(s) for this protective effect is (are) not known, We examined the tissue-specific effects of AT on oxidized LDL (ox-LDL)-mediated endothelial dysfunction in male New Zealand White rabbits. Animals consumed chow deficient in (< 10 IU/kg) or supplemented with (1,000 IU/kg) AT for 28 d. Exposure of thoracic aortae from AT-deficient animals to ox-LDL (0-500 mu g/ml) for 4 h produced dose-dependent inhibition of acetylcholine-mediated relaxation (P < 0.05) while vessels derived from animals consuming AT were resistant to ox-LDL-mediated endothelial dysfunction, Animals consuming AT demonstrated a 100-fold increase in vascular AT content and this was strongly correlated with vessel resistance to endothelial dysfunction from ox-LDL (R = 0.67; P = 0.0014), These results were not explained by an effect of AT on ox-LDL-mediated cytotoxicity by LDH assay or scanning electron microscopy, Vascular incorporation of AT did produce resistance to endothelial dysfunction from protein kinase C stimulation, an event that has been implicated in the vascular response to ox-LDL. Human aortic endothelial cells loaded with AT also demonstrated resistance to protein kinase C stimulation by both phorbol ester and ox-LDL, Thus, these data indicate that enrichment of vascular tissue with AT protects the vascular endothelium from ox-LDL-mediated dysfunction, at least in part, through the inhibition of protein kinase C stimulation. These findings suggest one potential mechanism for the observed beneficial effect of AT in preventing the clinical expression of coronary artery disease that is distinct from the antioxidant protection of LDL.
引用
收藏
页码:386 / 394
页数:9
相关论文
共 51 条
[1]   VITAMIN-E REVERSES CHOLESTEROL-INDUCED ENDOTHELIAL DYSFUNCTION IN THE RABBIT CORONARY CIRCULATION [J].
ANDERSSON, TLG ;
MATZ, J ;
FERNS, GAA ;
ANGGARD, EE .
ATHEROSCLEROSIS, 1994, 111 (01) :39-45
[2]   ENDOTHELIUM-DEPENDENT INHIBITION OF PLATELET-AGGREGATION [J].
AZUMA, H ;
ISHIKAWA, M ;
SEKIZAKI, S .
BRITISH JOURNAL OF PHARMACOLOGY, 1986, 88 (02) :411-415
[3]   ALPHA-TOCOPHEROL (VITAMIN-E) REGULATES VASCULAR SMOOTH-MUSCLE CELL-PROLIFERATION AND PROTEIN-KINASE-C ACTIVITY [J].
BOSCOBOINIK, D ;
SZEWCZYK, A ;
AZZI, A .
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 1991, 286 (01) :264-269
[4]  
BOSCOBOINIK D, 1991, J BIOL CHEM, V266, P6188
[5]  
BREDT DS, 1992, J BIOL CHEM, V267, P10976
[6]   IS VITAMIN-E THE ONLY LIPID-SOLUBLE, CHAIN-BREAKING ANTIOXIDANT IN HUMAN-BLOOD PLASMA AND ERYTHROCYTE-MEMBRANES [J].
BURTON, GW ;
JOYCE, A ;
INGOLD, KU .
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 1983, 221 (01) :281-290
[7]  
CASTAGNA M, 1982, J BIOL CHEM, V257, P7847
[8]   INHIBITION OF SMOOTH-MUSCLE CELL-PROLIFERATION AND PROTEIN-KINASE-C ACTIVITY BY TOCOPHEROLS AND TOCOTRIENOLS [J].
CHATELAIN, E ;
BOSCOBOINIK, DO ;
BARTOLI, GM ;
KAGAN, VE ;
GEY, FK ;
PACKER, L ;
AZZI, A .
BIOCHIMICA ET BIOPHYSICA ACTA, 1993, 1176 (1-2) :83-89
[9]   INACTIVATION OF ENDOTHELIAL DERIVED RELAXING FACTOR BY OXIDIZED LIPOPROTEINS [J].
CHIN, JH ;
AZHAR, S ;
HOFFMAN, BB .
JOURNAL OF CLINICAL INVESTIGATION, 1992, 89 (01) :10-18
[10]  
CHUNG BH, 1986, METHOD ENZYMOL, V128, P181