Peroxynitrite Mediates Diabetes-Induced Endothelial Dysfunction: Possible Role of Rho Kinase Activation

被引:59
作者
El-Remessy, Azza B. [1 ,2 ,3 ,4 ]
Tawfik, Huda E. [2 ,3 ,5 ]
Matragoon, Suraporn [1 ,4 ]
Pillai, Bindu [1 ,4 ]
Caldwell, Ruth B. [3 ,4 ]
Caldwell, R. William [2 ,3 ]
机构
[1] Univ Georgia, Coll Pharm, Program Clin & Expt Therapeut, Augusta, GA 30912 USA
[2] Med Coll Georgia, Dept Pharmacol & Toxicol, Augusta, GA 30912 USA
[3] Med Coll Georgia, Vasc Biol Ctr, Augusta, GA 30912 USA
[4] Charlie Norwood VA Med Ctr, Augusta, GA 30912 USA
[5] King Saud Univ, Riyadh 11451, Saudi Arabia
关键词
NITRIC-OXIDE SYNTHASE; TYROSINE NITRATION; DECOMPOSITION CATALYST; OXIDATIVE STRESS; NADPH OXIDASE; GROWTH-FACTOR; UP-REGULATION; CELLS; SUPEROXIDE; INHIBITION;
D O I
10.1155/2010/247861
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Endothelial dysfunction is characterized by reduced bioavailability of NO due to its inactivation to form peroxynitrite or reduced expression of eNOS. Here, we examine the causal role of peroxynitrite in mediating diabetes-induced endothelial dysfunction. Diabetes was induced by STZ-injection, and rats received the peroxynitrite decomposition catalyst (FeTTPs, 15 mg/Kg/day) for 4 weeks. Vasorelaxation to acetylcholine, oxidative-stress markers, RhoA activity, and eNOS expression were determined. Diabetic coronary arteries showed significant reduction in ACh-mediated maximal relaxation compared to controls. Diabetic vessels showed also significant increases in lipid-peroxides, nitrotyrosine, and active RhoA and 50% reduction in eNOS mRNA expression. Treatment of diabetic animals with FeTTPS blocked these effects. Studies in aortic endothelial cells show that high glucose or peroxynitrite increases the active RhoA kinase levels and decreases eNOS expression and NO levels, which were reversed with blocking peroxynitrite or Rho kinase. Together, peroxynitrite can suppress eNOS expression via activation of RhoA and hence cause vascular dysfunction.
引用
收藏
页数:9
相关论文
共 41 条
[1]   Early Intervention of Tyrosine Nitration Prevents Vaso-Obliteration and Neovascularization in Ischemic Retinopathy [J].
Abdelsaid, Mohammed A. ;
Pillai, Bindu A. ;
Matragoon, Suraporn ;
Prakash, Roshini ;
Al-Shabrawey, Mohamed ;
El-Remessy, Azza B. .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2010, 332 (01) :125-134
[2]   Roles of superoxide, peroxynitrite, and protein kinase C in the development of tolerance to nitroglycerin [J].
Abou-Mohamed, G ;
Johnson, JA ;
Jin, L ;
El-Remessy, AB ;
Do, K ;
Kaesemeyer, WH ;
Caldwell, RB ;
Caldwell, RW .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2004, 308 (01) :289-299
[3]   Peroxynitrite mediates retinal neurodegeneration by inhibiting nerve growth factor survival signaling in experimental and human diabetes [J].
Ali, Tayyeba K. ;
Matragoon, Suraporn ;
Pillai, Bindu A. ;
Liou, Gregory I. ;
El-Remessy, Azza B. .
DIABETES, 2008, 57 (04) :889-898
[4]  
ALI TK, DIABETOLOGI IN PRESS
[5]  
CHANDRA S, FASEB J IN PRESS
[6]   High glucose causes upregulation of cyclooxygenase-2 and alters prostanoid profile in human endothelial cells -: Role of protein kinase C and reactive oxygen species [J].
Cosentino, F ;
Eto, M ;
De Paolis, P ;
van der Loo, B ;
Bachschmid, M ;
Ullrich, V ;
Kouroedov, A ;
Gatti, CD ;
Joch, H ;
Volpe, M ;
Lüscher, TF .
CIRCULATION, 2003, 107 (07) :1017-1023
[7]   Diabetes and vascular disease -: Pathophysiology, clinical consequences, and medical therapy:: Part I [J].
Creager, MA ;
Lüscher, TF ;
Cosentino, F ;
Beckman, JA .
CIRCULATION, 2003, 108 (12) :1527-1532
[8]   Endothelial dysfunction in diabetes [J].
De Vriese, AS ;
Verbeuren, TJ ;
Van de Voorde, J ;
Lameire, NH ;
Vanhoutte, PM .
BRITISH JOURNAL OF PHARMACOLOGY, 2000, 130 (05) :963-974
[9]  
Deen WM, 2002, FASEB J, V16, P1144
[10]  
Drel VR, 2007, INT J MOL MED, V20, P783