Skip Navigation



Cardiovascular Research Advance Access [Accepted Manuscript] published online on March 24, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp100
This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
83/1/72    most recent
cvp100v2
cvp100v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Li, X.
Right arrow Articles by Peng, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Li, X.
Right arrow Articles by Peng, T.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Over-expression of calpastatin inhibits calpain activation and attenuates myocardial dysfunction during endotoxemia

Xiaoping Li1,2,3,*, Ying Li2,4,*, Limei Shan2,4, E. Shen2,4, Ruizhen Chen1 and Tianqing Peng2,3,4,{dagger}

1 Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
2 Critical Illness Research, Lawson Health Research Institute, London Health Sciences Center, London, Ontario, Canada
3 Departments of Pathology, London, Ontario, Canada
4 Departments of Medicine, University of Western Ontario, London, Ontario, Canada

{dagger} Correspondence to: Dr. Tianqing Peng, Critical Illness Research, Lawson Health Research Institute, VRL 6th Floor, A6-140, 800 Commissioners Road, London, Ontario, Canada N6A 4G5 Tel. (519) 685-8300 Ext. 55441. Fax (519) 685-8341. E-mail: tpeng2{at}uwo.ca

Aims: Lipopolysaccharide (LPS) induces cardiomyocyte caspase-3 activation and proinflammatory factors, in particular tumor necrosis factor-alpha (TNF-{alpha}) production, both of which contribute to myocardial dysfunction during sepsis. The present study was to investigate the roles of calpain/calpastatin system in cardiomyocyte caspase-3 activation, TNF-{alpha} expression, and myocardial dysfunction during LPS stimulation.

Methods and Results: In cultured adult rat cardiomyocytes, LPS (1µg/ml) induced calpain and caspase-3 activity, and up-regulated TNF-{alpha} expression. These effects of LPS were abrogated by over-expression of calpastatin, an endogenous calpain inhibitor, transfection of calpain-1 siRNA or various pharmacological calpain inhibitors. Furthermore, blocking gp91phox-NADPH oxidase prevented calpain and caspase-3 activation, and decreased TNF-{alpha} expression in LPS-stimulated cardiomyocytes. To investigate the role of calpastatin in endotoxemia, transgenic mice with calpastatin over-expression (CAST-Tg) and wild-type mice were treated with LPS (4 mg/kg, i.p.) or saline in the presence of calpain inhibitor-III (10 mg/kg, i.p.) for 4 hours, and their heart function was measured with a Langendorff system. Over-expression of calpastatin significantly attenuated myocardial dysfunction (P<0.05). Consistently, calpain activity, caspase-3 activity and TNF-{alpha} expression were also reduced in CAST-Tg and calpain inhibitor-III compared with wild-type and vehicle-treated hearts, respectively.

Conclusions: gp91phox-NADPH oxidase-mediated calpain-1 activation induces caspase-3 activation and TNF-{alpha} expression in cardiomyocytes during LPS stimulation. Over-expression of calpastatin inhibits calpain activation and improves myocardial function in endotoxemia. The present study suggests that targeting calpain/calpastatin system may be a potential therapeutic intervention for septic hearts.

Time for primary review: 46 Days

* These authors equally contributed to this study.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.