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Systemic delivery of BH4 anti-apoptotic peptide using CPPs prevents cardiac ischemia-reperfusion injuries in vivo.
MedLine Citation:
PMID:  21839124     Owner:  NLM     Status:  Publisher    
There is an obvious need to develop pharmacological strategies to protect the heart in patients suffering from acute myocardial infarction. Apoptosis was evidenced as a main contributor of myocardial ischemia-reperfusion (IR) injury. Our cardioprotective strategy was based on the use of four cell penetrating peptides (CPP: Tat, (RXR)4, Bpep and Pip2b) which were conjugated to the BH4-peptide, derived from the BH4 domain of the Bcl-xL anti-apoptotic protein. These CPP-BH4 conjugates were able to reduce staurosporine-induced apoptosis in primary cardiomyocytes in vitro. Although Pip2b-BH4 was more efficient in terms of cellular uptake, it was as efficient as Tat-BH4 for its anti-apoptotic activity. As required for potential therapeutic application their cardioprotective effects were evaluated in an in vivo mouse model of myocardial IR injury. Our results clearly show that a single low dose (1mg/kg) injection of Tat-BH4 and Pip2b-BH4 administered intravenously 5min before reperfusion was able to drastically reduce infarct size (~47%) and to inhibit apoptosis (~60%) in the left ventricle of treated mice. Importantly, these effects are not observed following the injection of CPP alone or scrambled version of BH4. This study evidences that the Pip2b CPP, designed for oligonucleotides translocation, as well as the widely used natural Tat CPP exhibit similar efficacy in vivo to deliver BH4 anti-apoptotic peptide to the reperfused myocardium and may thus become useful therapeutic tools to treat acute myocardial infarction in the clinical setting.
Prisca Boisguerin; Christelle Redt-Clouet; Alicia Franck-Miclo; Sana Licheheb; Joël Nargeot; Stéphanie Barrère-Lemaire; Bernard Lebleu
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-8-2
Journal Detail:
Title:  Journal of controlled release : official journal of the Controlled Release Society     Volume:  -     ISSN:  1873-4995     ISO Abbreviation:  -     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-8-15     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8607908     Medline TA:  J Control Release     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2011. Published by Elsevier B.V.
UMR 5235 CNRS, Universités Montpellier 1 et 2, Place Eugene Bataillon, 34095 Montpellier, France; Institut für Medizinische Immunologie, Charité Universitätsmedizin Berlin, Hessische Strasse 3-4, 10115 Berlin, Germany.
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