Cardiovascular Research Advance Access [Accepted Manuscript] published online on September 18, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn257
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Over-expression of a modified bifunctional apoptosis regulator protects against cardiac injury and doxorubicin-induced cardiotoxicity in transgenic mice
1 Cecile Cox Quillen Laboratory of Geriatrics James H. Quillen School of Medicine East Tennessee State University Johnson City, TN 37614
2 Institute of Chemical Toxicology, Wayne State University Detroit, MI 48201
3 Department of Pediatrics, National University of Singapore, Singapore, 119074
4 Burnham Institute for Medical Research, La Jolla, CA 92037
* Correspondence to Dr. Balvin H.L. Chua James H. Quillen College of Medicine East Tennessee State University Box 70,432 Johnson City, TN 37614 Telephone: 423 926 1171 Fax: 423 979 3408 Email: chua{at}etsu.edu
AIMS: BAR (bifunctional apoptosis regulator) is an endoplasmic reticulum (ER) protein that interacts with both the extrinsic and intrinsic apoptosis pathways. We hypothesize that over-expression of BAR
RING prevents apoptosis and injury following ischemia/reperfusion (I/R) and attenuates doxorubicin (DOX)-induced cardiotoxicity.
METHODS AND RESULTS: We generated a line of transgenic mice that carried a human BARRING transgene under the control of the mouse 
-myosin heavy chain promoter. The RING domain, which binds ubiquitin conjugating enzymes, was deleted to prevent auto-ubiquitination of BAR and allow accumulation of the BAR protein, which binds apoptosis regulating proteins. High levels of human BARRING transcripts and 42 KDa BARRING protein were expressed in the hearts of transgenic mice. When excised hearts were reperfused ex vivo for 45 min as Langendorff preparations after 45 min of global ischemia, the functional recovery of the hearts, expressed as left ventricular developed pressure x heart rate, was 23 ± 1.7% in the nontransgenic hearts compared to 51.5 ± 4.3% in the transgenic hearts (p < 0.05). For in vivo studies, mice were subjected to 50 min of ligation of the left descending anterior coronary artery followed by 4 h of reperfusion. The infarct sizes following I/R injury, expressed as the percentage of the area at risk, were significantly smaller in the transgenic mice than in the nontransgenic mice (29 ± 4% vs. 55 ± 4%, p < 0.05). In hearts of mice subjected to cardiac I/R injury, BAR transgenic hearts had significantly fewer in situ oligo ligation (ISOL)-positive cardiac cells (5.0 ± 0.4% vs. 13.4 ± 0.5%, p < 0.05). Over-expression of BARRING also significantly attenuated DOX-induced cardiac dysfunction and apoptosis.
CONCLUSIONS: Our results demonstrate that over-expression of BARRING renders the heart more resistant to I/R injury and DOX-induced cardiotoxicity, and this protection correlates with reduced cardiomyocyte apoptosis.
KEYWORDS transgenic mice; BAR; cardiac apoptosis; ischemia/reperfusion injury; doxorubicin-induced cardiotoxicity
Time for primary review: 15 days
# These authors contribute equally to this work
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Cardiovasc Res 2009 81: 1-2.
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