Location: Children's Nutrition Research CenterTitle: Sirtuin-3 (SIRT3) protein attenuates doxorubicin-induced oxidative stress and improves mitochondrial respiration in H9c2 cardiomyocytes Author
|Cheung, Kyle - University Of Manitoba|
|Cole, Laura - University Of Manitoba|
|Xiang, Bo - University Of Manitoba|
|Chen, Keyun - Children'S Nutrition Research Center (CNRC)|
|Ma, Xiuli - University Of Manitoba|
|Myal, Yvonne - University Of Manitoba|
|Hatch, Grant - University Of Manitoba|
|Tong, Qiang - Children'S Nutrition Research Center (CNRC)|
|Dolinsky, Vernon - University Of Manitoba|
Submitted to: Journal of Biological Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/10/2015
Publication Date: 4/1/2015
Citation: Cheung, K.G., Cole, L.K., Xiang, B., Chen, K., Ma, X., Myal, Y., Hatch, G.M., Tong, Q., Dolinsky, V.W. 2015. Sirtuin-3 (SIRT3) protein attenuates doxorubicin-induced oxidative stress and improves mitochondrial respiration in H9c2 cardiomyocytes. Journal of Biological Chemistry. 290:10981-10993.
Interpretive Summary: Doxorubicin (DOX) is a drug used in the treatment of many cancers. However, its heart-damaging side effect limits its clinical use. DOX is believed to be harmful to the heart by increasing heart production of free radicals. Sirtuin-3 (SIRT3) is a protein modifying enzyme activated by decreased food intake. SIRT3 is known to be able to suppress free radical levels. The purpose of this study was to determine whether SIRT3 prevents DOX-induced free radical production in the heart. We found giving DOX to mice suppressed SIRT3 expression in the heart. Cells lacking of SIRT3 produced significantly more free radicals in the presence of DOX. On the other hand, increasing the level of SIRT3 in heart cells attenuated the amount of DOX-induced free radical production and preserved heart cell function. Our results suggest that SIRT3 activation could be a potential therapy for DOX-induced heart dysfunction.
Technical Abstract: Doxorubicin (DOX) is a chemotherapeutic agent effective in the treatment of many cancers. However, cardiac dysfunction caused by DOX limits its clinical use. DOX is believed to be harmful to cardiomyocytes by interfering with the mitochondrial phospholipid cardiolipin and causing inefficient electron transfer resulting in the production of reactive oxygen species (ROS). Sirtuin-3 (SIRT3) is a class III lysine deacetylase that is localized to the mitochondria and regulates mitochondrial respiration and oxidative stress resistance enzymes such as superoxide dismutase-2 (SOD2). The purpose of this study was to determine whether SIRT3 prevents DOX-induced mitochondrial ROS production. Administration of DOX to mice suppressed cardiac SIRT3 expression, and DOX induced a dose-dependent decrease in SIRT3 and SOD2 expression in H9c2 cardiomyocytes. SIRT3-null mouse embryonic fibroblasts produced significantly more ROS in the presence of DOX compared with wild-type cells. Overexpression of wild-type SIRT3 increased cardiolipin levels and rescued mitochondrial respiration and SOD2 expression in DOX-treated H9c2 cardiomyocytes and attenuated the amount of ROS produced following DOX treatment. These effects were absent when a deacetylase-deficient SIRT3 was expressed in H9c2 cells. Our results suggest that overexpression of SIRT3 attenuates DOX-induced ROS production, and this may involve increased SOD2 expression and improved mitochondrial bioenergetics. SIRT3 activation could be a potential therapy for DOX-induced cardiac dysfunction.