Abstract 9928: Cardiac-specific Overexpression of High-mobility Group Box 1 Attenuates Cardiomyocyte Apoptosis and Mitochondrial Dysfunction During the Pathogenesis of Doxorubicin Cardiomyopathy
Background: The mechanism of doxorubicin cardiomyopathy is thought to be related to cardiomyocyte apoptosis, which contributes to development of myocardial loss and severe contractile dysfunction. High-mobility group box 1 (HMGB1) is a nuclear DNA-binding protein, as well as having the potential of inhibiting apoptosis. Purpose of this work is to clarify the role of cardiac HMGB1 in response to cardiomyocyte apoptosis.
Methods and Results: Doxorubicin was administrated in transgenic mice with cardiac-specific overexpression of HMGB1 (HMGB1-Tg) and wild-type littermate mice (WT). We evaluated the expression of heat shock protein B1 (HSPB1) which was reported to be a downstream target of HMGB1. Its expression was significantly higher in HMGB1-Tg mice compared with WT mice. Next, we assessed the localization of second mitochondria-derived activator of caspase (Smac), which is inhibited by HSPB1 and necessary for apoptosis in cardiomyocytes. Release of Smac from mitochondria was prevented in HMGB1-Tg mice compared with WT mice. Cardiomyocyte apoptosis were prevented in HMGB1-Tg mice. With electron microscopy, we observed distinguished mitochondrial damage and vacuolization in doxorubicin-treated WT, but not in HMGB1-Tg mice. Furthermore, the survival rate after doxorubicin administration of HMGB1-Tg mice was higher. In in vitro experiments, protein expression of cleaved caspase 3 which indicates the degree of apoptosis was higher in doxorubicin-treated HMGB1 knock down (HMGB1-KO) cardiomyocyte. In addition, protein expression of HSPB1 was lower in doxorubicin-treated HMGB1-KO cardiomyocyte. Moreover, we found that mitochondrial membrane potential evaluated by using 5,5’,6,6’-tetrachloro-1,1’,3,3’-tetraethylbenzimidazolylcarbocyanine iodide (JC-1) was markedly reduced in doxorubicin-treated HMGB1-KO cardiomyocyte.
Conclusion: We report the first in vivo and vitro evidence that cardiac HMGB1 attenuate cardiomyocyte apoptosis and mitochondrial dysfunction during the pathogenesis of doxorubicin cardiomyopathy. These results may provide a novel therapeutic approach for doxorubicin cardiomyopathy.
- © 2013 by American Heart Association, Inc.