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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Holthoff, Hans-peter Bott-flügel, Lorenz Schömig, Albert Grewe, Diana Laugwitz, Karl-ludwig Ott, Thomas Ungerer, Martin Moretti, Alessandra Seyfarth, Melchior Weig, Hans-jörg Gillitzer, Angelika |
| Description | Author Affiliation: Moretti A ( I. Medizinische Klinik and Deutsches Herzzentrum, D-81675 Munich, Germany.); |
| Abstract | Programmed cell death involves the activation of caspase proteases that can mediate the cleavage of vital cytoskeletal proteins. We have recently reported that, in failing cardiac myocytes, caspase-3 activation is associated with a reduction in contractile performance. In this study we used a modified yeast two-hybrid system to screen for caspase-3 interacting proteins of the cardiac cytoskeleton. We identified ventricular essential myosin light chain (vMLC1) as a target for caspase-3. By sequencing and site-directed mutagenesis, a noncanonical cleavage site for caspase-3 was mapped to the C-terminal DFVE(135)G motif. We demonstrated that vMLC1 cleavage in failing myocardium in vivo is associated with a morphological disruption of the organized vMLC1 staining of sarcomeres, and with a reduction in myocyte contractile performance. Adenoviral gene transfer of the caspase inhibitor p35 in vivo prevented caspase-3 activation and vMLC1 cleavage, with positive impact on contractility. These data suggest that direct cleavage of vMLC1 by activated caspase-3 may contribute to depression of myocyte function by altering cross-bridge interaction between myosin and actin molecules. Therefore, activation of apoptotic pathways in the heart may lead to contractile dysfunction before cell death. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 18 |
| Volume Number | 99 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2002-09-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Caspases Metabolism Heart Physiopathology Myocardium Myosin Light Chains Animals COS Cells Caspase 3 Hydrolysis Kinetics Mutagenesis, Site-Directed Enzymology Genetics Precipitin Tests Rabbits Sarcomeres Substrate Specificity Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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