恩帕吉菲
心脏毒性
阿霉素
药理学
医学
信号转导
癌症研究
化学
化疗
内科学
内分泌学
糖尿病
生物化学
2型糖尿病
作者
Hsien‐Yuan Chang,Hsiao-Chun Hsu,Yi‐Hsien Fang,Ping‐Yen Liu,Yen-Wen Liu
标识
DOI:10.1016/j.biopha.2024.116759
摘要
Sodium-glucose cotransporter-2 inhibitors, such as empagliflozin, are pivotal therapies for heart failure. However, the effect of empagliflozin on doxorubicin-related cardiac dysfunction remains unclear. Human induced pluripotent stem cell- and embryonic stem cell-derived cardiomyocytes were used to investigate the direct effect of empagliflozin on human cardiomyocytes. Then, the c-Jun amino-terminal kinases (JNK) inhibitor SP600125 was administered to the doxorubicin cardiotoxicity model in vitro and in vivo to investigate the role of JNK in empagliflozin. In human stem cell-derived cardiomyocytes, pretreatment with empagliflozin attenuated doxorubicin-induced cleavage of caspase 3 and other apoptosis markers. Empagliflozin significantly attenuated doxorubicin-induced phosphorylation of JNK and p38. Inhibiting the phosphorylation of JNK (SP600125) or STAT3 attenuated doxorubicin-induced apoptosis, but inhibiting the phosphorylation of p38 did not. SP600125 inhibits the phosphorylation of STAT3 (S727), and a STAT3 (Y705) inhibitor also inhibits the phosphorylation of JNK. Empagliflozin and SP600125 attenuated doxorubicin-induced increases in reactive oxygen species (ROS) and decreases in oxidized nicotinamide adenine dinucleotide (NAD+). In animal studies, empagliflozin and SP600125 attenuated doxorubicin-induced cardiac dysfunction and fibrosis. Empagliflozin attenuated doxorubicin-induced apoptosis by inhibiting the phosphorylation of JNK and its downstream signaling pathways, including ROS and NAD+.
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