Low shear stress preferentially enhances IKK activity through selective sources of ROS for persistent activation of NF-κB in endothelial cells

被引:59
作者
Mohan, Sumathy
Koyoma, Koichi
Thangasamy, Amalraj
Nakano, Hiroyasu
Glickman, Randolph D.
Mohan, Natarajan
机构
[1] Univ Texas, Hlth Sci Ctr, Dept Pathol, San Antonio, TX 78229 USA
[2] Univ Texas, Hlth Sci Ctr, Dept Ophthalmol, San Antonio, TX 78229 USA
[3] Univ Texas, Hlth Sci Ctr, Dept Radiat Oncol, San Antonio, TX 78229 USA
[4] Juntendo Univ, Sch Med, Dept Immunol, Tokyo 113, Japan
来源
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY | 2007年 / 292卷 / 01期
关键词
upstream kappa B kinases; laminar shear stress; oxidative stress; atherogenesis; reactive oxygen species;
D O I
10.1152/ajpcell.00535.2005
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
NF-kappa B signaling pathway has been known to play a major role in the pathological process of atherogenesis. Unlike high shear stress, in which the NF-kappa B activity is transient, our earlier studies have demonstrated a persistent activation of NF-kappa B in response to low shear stress in human aortic endothelial cells. These findings partially explained why low shear regions that exist at bifurcations of arteries are prone to atherosclerosis, unlike the relatively atheroprotective high shear regions. In the present study, we further investigated 1) the role of NF-kappa B signaling kinases (IKK alpha and beta) that may be responsible for the sustained activation of NF-kappa B in low shear stress and 2) the regulation of these kinases by reactive oxygen species (ROS). Our results demonstrate that not only is a significant proportion of low shear-induced-kinase activity is contributed by IKK beta, but it is also persistently induced for a prolonged time frame. The IKK activity (both alpha and beta) is blocked by apocynin (400 mu M), a specific NADPH oxidase inhibitor, and diphenyleneiodonium chloride (DPI; 10 mu M), an inhibitor of flavin-containing oxidases like NADPH oxidases. Determination of ROS also demonstrated an increased generation in low shear stress that could be blocked by DPI. These results suggest that the source of ROS generation in endothelial cells in response to low shear stress is NADPH oxidase. The DPI-inhibitable component of ROS is the primary regulator of specific upstream kinases that determine the persistent NF-kappa B activation selectively in low shear-induced endothelial cells.
引用
收藏
页码:C362 / C371
页数:10
相关论文
共 34 条
[21]   The role of the multidrug resistance protein-1 in modulation of endothelial cell oxidative stress [J].
Mueller, CFH ;
Widder, JD ;
McNally, JS ;
McCann, L ;
Jones, DP ;
Harrison, DG .
CIRCULATION RESEARCH, 2005, 97 (07) :637-644
[22]   Differential regulation of IκB kinase α and β by two upstream kinases, NF-κB-inducing kinase and mitogen-activated protein kinase ERK kinase kinase-1 [J].
Nakano, H ;
Shindo, M ;
Sakon, S ;
Nishinaka, S ;
Mihara, M ;
Yagita, H ;
Okumura, K .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (07) :3537-3542
[23]   Lead exposure raises superoxide and hydrogen peroxide in human endothelial and vascular smooth muscle cells [J].
Ni, ZM ;
Hou, S ;
Barton, CH ;
Vaziri, ND .
KIDNEY INTERNATIONAL, 2004, 66 (06) :2329-2336
[24]   Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage [J].
Nishikawa, T ;
Edelstein, D ;
Du, XL ;
Yamagishi, S ;
Matsumura, T ;
Kaneda, Y ;
Yorek, MA ;
Beebe, D ;
Oates, PJ ;
Hammes, HP ;
Giardino, I ;
Brownlee, M .
NATURE, 2000, 404 (6779) :787-790
[25]   Activation of the heterodimeric IκB kinase α (IKKα)-IKKβ complex is directional:: IKKα regulates IKKβ under both basal and stimulated conditions [J].
O'Mahony, A ;
Lin, X ;
Geleziunas, R ;
Greene, WC .
MOLECULAR AND CELLULAR BIOLOGY, 2000, 20 (04) :1170-1178
[26]   N-acetylcysteine suppresses TNF-induced NF-κB activation through inhibition of IκB kinases [J].
Oka, S ;
Kamata, H ;
Kamata, K ;
Yagisawa, H ;
Hirata, H .
FEBS LETTERS, 2000, 472 (2-3) :196-202
[27]   REACTIVE OXYGEN INTERMEDIATES AS APPARENTLY WIDELY USED MESSENGERS IN THE ACTIVATION OF THE NF-KAPPA-B TRANSCRIPTION FACTOR AND HIV-1 [J].
SCHRECK, R ;
RIEBER, P ;
BAEUERLE, PA .
EMBO JOURNAL, 1991, 10 (08) :2247-2258
[28]   DITHIOCARBAMATES AS POTENT INHIBITORS OF NUCLEAR FACTOR KAPPA-B ACTIVATION IN INTACT-CELLS [J].
SCHRECK, R ;
MEIER, B ;
MANNEL, DN ;
DROGE, W ;
BAEUERLE, PA .
JOURNAL OF EXPERIMENTAL MEDICINE, 1992, 175 (05) :1181-1194
[29]   The IKK/NF-κB pathway [J].
Senftleben, U ;
Karin, M .
CRITICAL CARE MEDICINE, 2002, 30 (01) :S18-S26
[30]   N-methyl-D-aspartate receptor activation in human cerebral endothelium promotes intracellular oxidant stress [J].
Sharp, CD ;
Houghton, J ;
Elrod, JW ;
Warren, A ;
Jackson, TH ;
Jawahar, A ;
Nanda, A ;
Minagar, A ;
Alexander, JS .
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2005, 288 (04) :H1893-H1899