Activated protein C inhibits tissue plasminogen activator-induced brain hemorrhage

被引：225

作者：

Cheng, Tong

Petraglia, Anthony L.

Li, Zhang

Thiyagarajan, Meenakshisundaram

Zhong, Zhihui

Wu, Zhenhua

Liu, Dong

Maggirwar, Sanjay B.

Deane, Rashid

Fernandez, Jose A.

LaRue, Barbra

Griffin, John H.

Chopp, Michael

Zlokovic, Berislav V.

机构：

[1] Univ Rochester, Med Ctr, Frank P Smith Lab Neurosci & Neurosurg Res, Dept Neurosurg, Rochester, NY 14642 USA

[2] Henry Ford Hlth Sci Ctr, Dept Neurol, Detroit, MI 48202 USA

[3] Univ Rochester, Med Ctr, Dept Microbiol & Immunol, Rochester, NY 14642 USA

[4] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA

来源：

NATURE MEDICINE | 2006年 / 12卷 / 11期

关键词：

D O I：

10.1038/nm1498

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Brain hemorrhage is a serious complication of tissue plasminogen activator (tPA) therapy for ischemic stroke. Here we report that activated protein C (APC), a plasma serine protease with systemic anticoagulant, anti- inflammatory and antiapoptotic activities, and direct vasculoprotective and neuroprotective activities, blocks tPA- mediated brain hemorrhage after transient brain ischemia and embolic stroke in rodents. We show that APC inhibits a pro- hemorrhagic tPA- induced, NF-kappa B-dependent matrix metalloproteinase-9 pathway in ischemic brain endothelium in vivo and in vitro by acting through protease-activated receptor 1. The present findings suggest that APC may improve thrombolytic therapy for stroke, in part, by reducing tPA- mediated hemorrhage.

引用

页码：1278 / 1285

页数：8

共 42 条

[1] Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia [J].

Asahi, M ;

Wang, XY ;

Mori, T ;

Sumii, T ;

Jung, JC ;

Moskowitz, MA ;

Fini, ME ;

Lo, EH .

JOURNAL OF NEUROSCIENCE, 2001, 21 (19) :7724-7732

[2] Efficacy and safety of recombinant human activated protein C for severe sepsis. [J].

Bernard, GR ;

Vincent, JL ;

Laterre, P ;

LaRosa, SP ;

Dhainaut, JF ;

Lopez-Rodriguez, A ;

Steingrub, JS ;

Garber, GE ;

Helterbrand, JD ;

Ely, EW ;

Fisher, CJ .

NEW ENGLAND JOURNAL OF MEDICINE, 2001, 344 (10) :699-709

[3] Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke [J].

Brott, T ;

Broderick, J ;

Kothari, R ;

ODonoghue, M ;

Barsan, W ;

Tomsick, T ;

Spilker, J ;

Miller, R ;

Sauerbeck, L ;

Farrell, J ;

Kelly, J ;

Perkins, T ;

Miller, R ;

McDonald, T ;

Rorick, M ;

Hickey, C ;

Armitage, J ;

Perry, C ;

Thalinger, K ;

Rhude, R ;

Schill, J ;

Becker, PS ;

Heath, RS ;

Adams, D ;

Reed, R ;

Klei, M ;

Hughes, A ;

Anthony, J ;

Baudendistel, D ;

Zadicoff, C ;

Rymer, M ;

Bettinger, I ;

Laubinger, P ;

Schmerler, M ;

Meiros, G ;

Lyden, P ;

Dunford, J ;

Zivin, J ;

Rapp, K ;

Babcock, T ;

Daum, P ;

Persona, D ;

Brody, M ;

Jackson, C ;

Lewis, S ;

Liss, J ;

Mahdavi, Z ;

Rothrock, J ;

Tom, T ;

Zweifler, R .

STROKE, 1997, 28 (11) :2109-2118

[4] Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective [J].

Cheng, T ;

Liu, D ;

Griffin, JH ;

Fernández, JA ;

Castellino, F ;

Rosen, ED ;

Fukudome, K ;

Zlokovic, BV .

NATURE MEDICINE, 2003, 9 (03) :338-342

[5] LRP/amyloid β-peptide interaction mediates differential brain efflux of Aβ isoforms [J].

Deane, R ;

Wu, ZH ;

Sagare, A ;

Davis, J ;

Yan, SD ;

Hamm, K ;

Xu, F ;

Parisi, M ;

LaRue, B ;

Hu, HW ;

Spijkers, P ;

Guo, H ;

Song, XM ;

Lenting, PJ ;

Van Nostrand, WE ;

Zlokovic, BV .

NEURON, 2004, 43 (03) :333-344

[6] Activated protein C alters cytosolic calcium flux in human brain endothelium via binding to endothelial protein C receptor and activation of protease activated receptor-1 [J].

Dömötör, E ;

Benzakour, O ;

Griffin, JH ;

Yule, D ;

Fukudome, K ;

Zlokovic, BV .

BLOOD, 2003, 101 (12) :4797-4801

[7] Endothelial barrier protection by activated protein C through PAR1-dependent sphingosine 1-phosphate receptor-1 crossactivation [J].

Feistritzer, C ;

Riewald, M .

BLOOD, 2005, 105 (08) :3178-3184

[8] Recombinant murine-activated protein C is neuroprotective in a murine ischemic stroke model [J].

Fernández, JA ;

Xu, X ;

Liu, D ;

Zlokovic, BV ;

Griffin, JH .

BLOOD CELLS MOLECULES AND DISEASES, 2003, 30 (03) :271-276

[9] Activated protein C mediates novel lung endothelial barrier enhancement - Role of sphingosine 1-phosphate receptor transactivation [J].

Finigan, JH ;

Dudek, SM ;

Singleton, PA ;

Chiang, ET ;

Jacobson, JR ;

Camp, SM ;

Ye, SQ ;

Garcia, JGN .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (17) :17286-17293

[10] S-nitrosylation of matrix metalloproteinases: Signaling pathway to neuronal cell death [J].

Gu, ZZ ;

Kaul, M ;

Yan, BX ;

Kridel, SJ ;

Cui, JK ;

Strongin, A ;

Smith, JW ;

Liddington, RC ;

Lipton, SA .

SCIENCE, 2002, 297 (5584) :1186-1190

← 1 2 3 4 5 →