Abstract 15265: Cardiac-Specific Overexpression of High-Mobility Group Box 1 Protects Cardiomyocyte from Apoptosis During the Pathogenesis of Doxorubicin Cardiomyopathy
Background: Anthracycline derivative doxorubicin is widely used to treat various types of cancer whose main clinical limitation is cardiotoxicity. The mechanism of this cardiotoxicity is thought to be related to cardiomyocyte apoptosis. Cardiomyocyte apoptosis contributes to the development of myocardial loss and severe contractile dysfunction during the pathogenesis of doxorubicin cardiomyopathy. High-mobility group box 1 (HMGB1) is a nuclear DNA-binding protein, as well as having the potential of inhibiting apoptosis. To test the hypothesis that HMGB1 protects cardiomyocyte from apoptosis, we studied doxorubicin cardiomyopathy using transgenic mice with cardiac-specific overexpression of HMGB1 (HMGB1-Tg).
Methods and Results: Doxorubicin was administrated in HMGB1-Tg mice and wild-type littermate (Wt) mice. We assessed the localization of second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI (Smac/DIABLO) which is necessary for apoptosis in cardiomyocytes and released from mitochondria into cytosol in response to apoptotic stimulation. Release of Smac/DIABLO from mitochondria was prevented in HMGB1-Tg mice compared with Wt mice. We evaluated the expression of heat shock protein B1 (HSPB1) which was reported to be a downstream target of HMGB1 and inhibit the release of Smac/DIABLO from mitochondria. Its expression was significantly higher in HMGB1-Tg mice than in Wt mice. Cardiomyocyte apoptosis was detected by using TUNEL stain demonstrated that cardiomyocyte apoptosis were prevented in HMGB1-Tg mice after doxorubicin treatment. Furthermore, the survival rate after doxorubicin administration of HMGB1-Tg mice was higher than that of Wt mice.
Conclusion: We report the first in vivo evidence that cardiac-specific overexpression of HMGB1 protects cardiomyocyte from apoptosis during the pathogenesis of doxorubicin cardiomyopathy through regulating the protein level of HSPB1 and release of Smac/DIABLO from mitochondria. These results may provide a novel therapeutic approach for doxorubicin cardiomyopathy.
- © 2012 by American Heart Association, Inc.