Salidroside improves doxorubicin-induced cardiac dysfunction by suppression of excessive oxidative stress and cardiomyocyte apoptosis.
Doxorubicin (DOX) is a potent available antitumor drug; however, its clinical use is limited by the cardiotoxicity. Salidroside (SLD), with strong antioxidative and cytoprotective actions, is of particular interest in the development of antioxidative therapies for oxidative injury in cardiac diseases. Now, the protection and underlying mechanisms of SLD against DOX-induced cardiotoxicity are still unknown. In the present study, we revealed both antioxidative mechanism and Bcl2-dependent survival signaling involved in SLD's protection. We observed that DOX exposure induced mortality elevation, body weight loss, and cardiac dysfunction in mice, increased lactate dehydrogenase leakage and cardiomyocyte apoptosis, but decreased cell viability and size in cardiac tissues and cultured H9c2 cells, respectively, which were effectively antagonized by SLD supplement. We further observed that SLD significantly reduced the intercellular oxidative stress level, partly by inhibiting NOX1 expression and augmenting the expression and activities of the endogenous antioxidative enzymes, catalase, and manganese superoxide dismutase. In addition, SLD treatment upregulated the antiapoptotic Bcl2 and downregulated the proapoptotic Bax and inhibited a downstream pathway of Bcl2/Bax and caspase-3 activity. Our results indicated that SLD effectively protected the cardiomyocytes against DOX-induced cardiotoxicity by suppressing the excessive oxidative stress and activating a Bcl2-mediated survival signaling pathway.
*School of Life Sciences and Bioengineering, Southwest Jiaotong University, Chengdu, China; †Molecular Medicine Research Center, State Key Laboratory of Biotherapy; and ‡Department of Cardiology, West China Hospital, Sichuan University, Chengdu, China.
Xu-Lei
XL
Wang
Xue
X
Wang
Li-Li
LL
Xiong
Ye
Y
Zhu
Hua-Li
HL
Chen
Jia-Xiang
JX
Chen
Xiao-Xiao
XX
Wang
Ru-Li
RL
Li
Zhi-Yun
ZY
Guo
Ping
P
Li
Wei
W
Jiang
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D048429:Cell Size / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002999:Clone Cells; D004317:Doxorubicin / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005960:Glucosides / Q000494:pharmacology / Q000627:therapeutic use*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D018754:Ventricular Dysfunction / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*
D000903:Antibiotics, Antineoplastic; D000975:Antioxidants; D002316:Cardiotonic Agents; D005960:Glucosides; D010636:Phenols; D004317:Doxorubicin; D010088:Oxidoreductases; C009172:rhodioloside