Document Detail


Effective blockage of both the extrinsic and intrinsic pathways of apoptosis in mice by TAT-crmA.
MedLine Citation:
PMID:  20427266     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Evidence accumulates that in clinically relevant cell death, both the intrinsic and extrinsic apoptotic pathway synergistically contribute to organ failure. In search for an inhibitor of apoptosis that provides effective blockage of these pathways, we analyzed viral proteins that evolved to protect the infected host cells. In particular, the cowpox virus protein crmA has been demonstrated to be capable of blocking key caspases of both pro-apoptotic pathways. To deliver crmA into eukaryotic cells, we fused the TAT protein transduction domain of HIV to the N terminus of crmA. In vitro, the TAT-crmA fusion protein was efficiently translocated into target cells and inhibited apoptosis mediated through caspase-8, caspase-9, and caspase-3 after stimulation with alpha-Fas, etoposide, doxorubicin, or staurosporine. The extrinsic apoptotic pathway was investigated following alpha-Fas stimulation. In vivo 90% of TAT-crmA-treated animals survived an otherwise lethal dose of alpha-Fas and showed protection from Fas-induced organ failure. To examine the intrinsic apoptotic pathway, we investigated the survival of mice treated with an otherwise lethal dose of doxorubicin. Whereas all control mice died within 31 days, 40% of mice that concomitantly received intraperitoneal injections of TAT-crmA survived. To test the ability to comprehensively block both the intrinsic and extrinsic apoptotic pathway in a clinically relevant setting, we employed a murine cardiac ischemia-reperfusion model. TAT-crmA reduced infarction size by 40% and preserved left ventricular function. In summary, these results provide a proof of principle for the inhibition of apoptosis with TAT-crmA, which might provide a new treatment option for ischemia-reperfusion injuries.
Authors:
Stefan Krautwald; Ekkehard Ziegler; Lars Rölver; Andreas Linkermann; Kirsten A Keyser; Philip Steen; Kai C Wollert; Mortimer Korf-Klingebiel; Ulrich Kunzendorf
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Publication Detail:
Type:  Journal Article     Date:  2010-04-28
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-06-21     Completed Date:  2010-08-24     Revised Date:  2011-08-01    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  19997-20005     Citation Subset:  IM    
Affiliation:
Division of Nephrology and Hypertension, University of Kiel, 24105 Kiel, Germany.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens, CD95 / pharmacology
Antineoplastic Agents / pharmacology
Apoptosis / drug effects,  genetics,  physiology*
Caspases / antagonists & inhibitors,  metabolism
Doxorubicin / pharmacology
Etoposide / pharmacology
Female
Green Fluorescent Proteins / genetics,  metabolism
Humans
Immunoblotting
Jurkat Cells
Male
Membrane Potential, Mitochondrial / drug effects
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Microscopy, Fluorescence
Myocardial Infarction / physiopathology,  prevention & control
Myocytes, Cardiac / cytology,  drug effects,  metabolism
Recombinant Fusion Proteins / metabolism*,  pharmacology
Serpins / genetics,  metabolism*,  pharmacology
Signal Transduction / drug effects,  genetics,  physiology*
Survival Analysis
Viral Proteins / genetics,  metabolism*,  pharmacology
tat Gene Products, Human Immunodeficiency Virus / genetics,  metabolism
Chemical
Reg. No./Substance:
0/Antigens, CD95; 0/Antineoplastic Agents; 0/Recombinant Fusion Proteins; 0/Serpins; 0/Viral Proteins; 0/tat Gene Products, Human Immunodeficiency Virus; 147336-22-9/Green Fluorescent Proteins; 23214-92-8/Doxorubicin; 33419-42-0/Etoposide; 96282-35-8/interleukin-1beta-converting enzyme inhibitor; EC 3.4.22.-/Caspases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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