Hydrogen sulfide protects H9c2 cells against doxorubicin-induced cardiotoxicity through inhibition of endoplasmic reticulum stress.
The roles of hydrogen sulfide (H(2)S) and endoplasmic reticulum (ER) stress in doxorubicin (DOX)-induced cardiotoxicity are still unclear. This study aimed to dissect the hypothesis that H(2)S could protect H9c2 cells against DOX-induced cardiotoxicity by inhibiting ER stress. Our results showed that exposure of H9c2 cells to DOX significantly inhibited the expression and activity of cystathionine-γ-lyase (CSE), a synthetase of H(2)S, accompanied by the decreased cell viability and the increased reactive oxygen species (ROS) accumulation. In addition, exposure of cells to H(2)O(2) (an exogenous ROS) mimicked the inhibitory effect of DOX on the expression and activity of CSE. Pretreatment with N-acetyl-L: -cysteine (NAC) (a ROS scavenger) attenuated intracellular ROS accumulation, cytotoxicity, and the inhibition of expression and activity of CSE induced by DOX. Notably, the ER stress-related proteins, including glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) were obviously upregulated in DOX-treated H9c2 cells. Pretreatment with sodium hydrosulfide (NaHS, a H(2)S donor) before DOX exposure markedly suppressed DOX-induced overexpressions of GRP78 and CHOP, cytotoxicity and oxidative stress. In conclusion, we have demonstrated that ROS-mediated inhibition of CSE is involved in DOX-induced cytotoxicity in H9c2 cells, and that exogenous H(2)S can confer protection against DOX-induced cardiotoxicity partly through inhibition of ER stress.
Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
Xiu-Yu
XY
Wang
Chun-Tao
CT
Yang
Dong-Dan
DD
Zheng
Li-Qiu
LQ
Mo
Ai-Ping
AP
Lan
Zhan-Li
ZL
Yang
Fen
F
Hu
Pei-Xi
PX
Chen
Xin-Xue
XX
Liao
Jian-Qiang
JQ
Feng
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003542:Cystathionine gamma-Lyase / Q000378:metabolism; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D016166:Free Radical Scavengers / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000633:toxicity; D006862:Hydrogen Sulfide / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016877:Oxidants / Q000633:toxicity; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013440:Sulfides / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP
D000111:Acetylcysteine; D000903:Antibiotics, Antineoplastic; D000975:Antioxidants; D003542:Cystathionine gamma-Lyase; D004317:Doxorubicin; D016166:Free Radical Scavengers; D006360:Heat-Shock Proteins; D006861:Hydrogen Peroxide; D006862:Hydrogen Sulfide; D016877:Oxidants; D017382:Reactive Oxygen Species; D013440:Sulfides; D051742:Transcription Factor CHOP; C497251:Ddit3 protein, rat; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C025451:sodium bisulfide