Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: Empagliflozin attenuated doxorubicin-induced apoptosis by inhibiting the phosphorylation of JNK and its downstream signaling pathways, including ROS and NAD+.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: Empagliflozin attenuated doxorubicin-induced apoptosis by inhibiting the phosphorylation of JNK and its downstream signaling pathways, including ROS and NAD+.
摘要：
背景：钠-葡萄糖协同转运蛋白-2抑制剂，比如empagliflozin,是心力衰竭的关键疗法。然而,依帕格列净对阿霉素相关心功能不全的影响尚不清楚.
方法：使用人诱导多能干细胞和胚胎干细胞衍生的心肌细胞来研究依帕格列净对人心肌细胞的直接作用。然后，在体外和体内将c-Jun氨基末端激酶(JNK)抑制剂SP600125应用于阿霉素心脏毒性模型,以研究JNK在依帕列净中的作用.
结果：在人类干细胞衍生的心肌细胞中，用依帕格列净预处理可减弱阿霉素诱导的caspase3和其他凋亡标志物的裂解。Empagliflozin显着减弱了阿霉素诱导的JNK和p38磷酸化。抑制JNK（SP600125）或STAT3的磷酸化减弱阿霉素诱导的细胞凋亡，但抑制p38的磷酸化没有。SP600125抑制STAT3的磷酸化（S727），和STAT3(Y705)抑制剂也抑制JNK的磷酸化。Empagliflozin和SP600125减弱了阿霉素诱导的活性氧（ROS）增加和氧化型烟酰胺腺嘌呤二核苷酸（NAD）减少。在动物研究中,依帕格列净和SP600125可以减轻阿霉素诱导的心脏功能障碍和纤维化。
结论：Empagliflozin通过抑制JNK及其下游信号通路的磷酸化减弱阿霉素诱导的细胞凋亡，包括ROS和NAD+。
方法：使用人诱导多能干细胞和胚胎干细胞衍生的心肌细胞来研究依帕格列净对人心肌细胞的直接作用。然后，在体外和体内将c-Jun氨基末端激酶(JNK)抑制剂SP600125应用于阿霉素心脏毒性模型,以研究JNK在依帕列净中的作用.
结果：在人类干细胞衍生的心肌细胞中，用依帕格列净预处理可减弱阿霉素诱导的caspase3和其他凋亡标志物的裂解。Empagliflozin显着减弱了阿霉素诱导的JNK和p38磷酸化。抑制JNK（SP600125）或STAT3的磷酸化减弱阿霉素诱导的细胞凋亡，但抑制p38的磷酸化没有。SP600125抑制STAT3的磷酸化（S727），和STAT3(Y705)抑制剂也抑制JNK的磷酸化。Empagliflozin和SP600125减弱了阿霉素诱导的活性氧（ROS）增加和氧化型烟酰胺腺嘌呤二核苷酸（NAD）减少。在动物研究中,依帕格列净和SP600125可以减轻阿霉素诱导的心脏功能障碍和纤维化。
结论：Empagliflozin通过抑制JNK及其下游信号通路的磷酸化减弱阿霉素诱导的细胞凋亡，包括ROS和NAD+。
