Caveolin-1 Regulates Rac1 Activation and Rat Pulmonary Microvascular Endothelial Hyperpermeability Induced by TNF-α

被引:16
作者
Shao, Min [1 ,2 ]
Yue, Yang [1 ]
Sun, Geng-Yun [1 ]
You, Qing-Hai [1 ]
Wang, Nan [1 ]
Zhang, Dan [1 ]
机构
[1] Anhui Med Univ, Affiliated Hosp 1, Dept Resp Med, Hefei, Anhui, Peoples R China
[2] Anhui Med Univ, Dept Crit Care Med, Anhui Prov Hosp, Hefei, Anhui, Peoples R China
基金
中国国家自然科学基金;
关键词
NF-KAPPA-B; RHO-GTPASES; INTRACELLULAR CA2+; CELL POLARIZATION; BARRIER INTEGRITY; REACTIVE OXYGEN; SMOOTH-MUSCLE; NITRIC-OXIDE; PERMEABILITY; KINASE;
D O I
10.1371/journal.pone.0055213
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
A multiplicity of vital cellular and tissue level functions are controlled by caveolin-1 and it is considered to be an important candidate for targeted therapeutics. Rac1-cortactin signaling plays an important role in maintaining the functions of the endothelial barrier in microvascular endothelial cells. The activity of Rac1 has been shown to be regulated by caveolin-1. Therefore, the present study investigated the consequences of down-regulating caveolin-1 and the subsequent changes in activity of Rac1 and the endothelial barrier functions in primary rat pulmonary microvascular endothelial cells (RPMVECs). RPMVECs were transfected with a small hairpin RNA duplex to down-regulate caveolin-1 expression. This procedure significantly increased the activity of Rac1. Moreover, down-regulation of caveolin-1 attenuated TNF-alpha-induced decrease in TER, increase in the flux of FITC-BSA and the disappearance of cortactin from the cell periphery in RPMVEC. Rac1 inhibitors significantly abolished this barrier-protective effect induced by down-regulation of caveolin-1 in response to TNF-alpha in RPMVECs. In conclusion, our data suggest a mechanism for the regulation of Rac1 activity by caveolin-1, with consequences for activation of endothelial cells in response to TNF-alpha.
引用
收藏
页数:12
相关论文
共 60 条
[31]   Caveolin regulation of endothelial function [J].
Minshall, RD ;
Sessa, WC ;
Stan, RV ;
Anderson, RGW ;
Malik, AB .
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 2003, 285 (06) :L1179-L1183
[32]   Semaphorin SEMA317 and VEGF have opposing effects on cell attachment and spreading [J].
Nasarre, P ;
Constantin, B ;
Rouhaud, L ;
Harnois, T ;
Raymond, G ;
Drabkin, HA ;
Bourmeyster, N ;
Roche, J .
NEOPLASIA, 2003, 5 (01) :83-92
[33]   Focal-adhesion targeting links caveolin-1 to a Rac1-degradation pathway [J].
Nethe, Micha ;
Anthony, Eloise C. ;
Fernandez-Borja, Mar ;
Dee, Rob ;
Geerts, Dirk ;
Hensbergen, Paul J. ;
Deelder, Andre M. ;
Schmidt, Gudula ;
Hordijk, Peter L. .
JOURNAL OF CELL SCIENCE, 2010, 123 (11) :1948-1958
[34]   Live dynamic imaging of caveolae pumping targeted antibody rapidly and specifically across endothelium in the lung [J].
Oh, Phil ;
Borgstrom, Per ;
Witkiewicz, Halina ;
Li, Yan ;
Borgstrom, Bengt J. ;
Chrastina, Adrian ;
Iwata, Koji ;
Zinn, Kurt R. ;
Baldwin, Richard ;
Testa, Jacqueline E. ;
Schnitzer, Jan E. .
NATURE BIOTECHNOLOGY, 2007, 25 (03) :327-337
[35]   Caveolae: From cell biology to animal physiology [J].
Razani, B ;
Woodman, SE ;
Lisanti, MP .
PHARMACOLOGICAL REVIEWS, 2002, 54 (03) :431-467
[36]   Caveolin-1 in cytokine-induced enhancement of intracellular Ca2+ in human airway smooth muscle [J].
Sathish, Venkatachalem ;
Abcejo, Amard J. ;
VanOosten, Sarah Kay ;
Thompson, Michael A. ;
Prakash, Y. S. ;
Pabelick, Christina M. .
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 2011, 301 (04) :L607-L614
[37]   Impaired cAMP and Rac 1 Signaling Contribute to TNF--induced Endothelial Barrier Breakdown in Microvascular Endothelium [J].
Schlegel, Nicolas ;
Waschke, Jens .
MICROCIRCULATION, 2009, 16 (06) :521-533
[38]   Caveolae-deficient endothelial cells show defects in the uptake and transport of albumin in vivo [J].
Schubert, W ;
Frank, PG ;
Razani, B ;
Park, DS ;
Chow, CW ;
Lisanti, MP .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (52) :48619-48622
[39]   Rac1 function is required for Src-induced transformation - Evidence of a role for Tiam1 and Vav2 in RAC activation by Src [J].
Servitja, JM ;
Marinissen, MJ ;
Sodhi, A ;
Bustelo, XR ;
Gutkind, JS .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (36) :34339-34346
[40]   Escherichia coli K1 internalization via caveolae requires caveolin-1 and protein kinase Cα interaction in human brain microvascular endothelial cells [J].
Sukumaran, SK ;
Quon, MJ ;
Prasadarao, NV .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (52) :50716-50724