Empagliflozin attenuates doxorubicin-induced cardiotoxicity by inhibiting the JNK signaling pathway - 16/06/24
, Yen-Wen Liu b, c, d, ⁎ 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+.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | Empagliflozin attenuate doxorubicin-induced cardiotoxicity in hiPSC-CM. |
• | Empagliflozin attenuate doxorubicin-induced cardiac dysfunction in mice. |
• | The mechanism might involve the inhibition of pJNK/STAT3 signaling pathways. |
• | Downstream signaling pathways potentially implicated include ROS and NAD+. |
Abbreviations : AFSC-iPS-CM,, BSA,, CTRCD,, DAPI,, EF,, Ees,, FS,, hiPSC-CM,, hSC-CM,, JC-1,, JNK, HIF-1α,, LV,, NAD+,, NADH,, OCR,, PBS,, PV,, ROS,, RUES2-CM,, SGLT,, STAT3,
Keywords : hiPSC-CM, Doxorubicin, Empagliflozin, SGLT2 inhibitor, Cardiotoxicity, JNK, Human induced pluripotent stem cell-derived cardiomyocyte, Human embryonic stem cell-derived cardiomyocytes
Plan
Vol 176
Article 116759- juillet 2024 Retour au numéro
Article précédent
- Identification of a novel hypoglycemic small molecule, trans-2, 4-dimethoxystilbene by rectifying gut microbiota and activating hepatic AMPKα-PPARγ pathway through gut-liver axis
- Zi-jing Wang, Peng Ma, Chun-yang Xu, Tian-shu Xu, Li Zhang, Ping He, Bi-yu Hou, Xiu-ying Yang, Guan-hua Du, Teng-fei Ji, Gui-fen Qiang
- Reynoutria japonica consisted of emodin-8-β-D-glucoside ameliorates Dermatophagoides farinae extract-induced atopic dermatitis-like skin inflammation in mice by inhibiting JAK/STAT signaling
- Ki-Shuk Shim, Hyun‑Kyung Song, Musun Park, Hye Jin Kim, Seol Jang, Taesoo Kim, Ki Mo Kim
Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.
Déjà abonné à cette revue ?