Levosimendan Protects against Doxorubicin-Induced Cardiotoxicity by Regulating the PTEN/Akt Pathway

Abstract

Background and Aims. Myocyte apoptosis plays a critical role in the development of doxorubicin- (DOX-) induced cardiotoxicity. In addition to its cardiotonic effect, laboratory evidence indicates that levosimendan can inhibit apoptosis, but its role in DOX-induced cardiac injury remains unclear. Therefore, the present study is aimed at exploring whether levosimendan could attenuate DOX-induced cardiotoxicity. Methods. Levosimendan (1 mg/kg) was administered to mice through oral gavage once daily for 4 weeks, and the mice were also subjected to an intraperitoneal injection of DOX (5 mg/kg) or saline, once a week for 4 weeks, to create a chronic model of DOX-induced cardiotoxicity. A morphological examination and biochemical analysis were used to evaluate the effects of levosimendan. H9C2 cells were used to verify the protective role of levosimendan in vitro. And an Akt inhibitor was utilized to verify the cardioprotection of levosimendan. Results. Levosimendan reduced the cardiac dysfunction and attenuated the myocardial apoptosis induced by DOX in vivo and in vitro. Levosimendan also inhibited the activation of phosphatase and tensin homolog (PTEN) and upregulated P-Akt expression both in vivo and in vitro. And inhibition of Akt abolished the cardioprotection of levosimendan in vitro. Conclusion. Levosimendan may protect against DOX-induced cardiotoxicity via modulation of the PTEN/Akt signaling pathway.

Levosimendan Postconditioning Attenuates Cardiomyocyte Apoptosis after Myocardial Infarction

“…Levosimendan preconditioning has been shown to protect cardiomyocytes against apoptosis [ 9 – 13 ]. Moreover, it exerted comparable antiapoptotic effects in organs such as the liver, lungs, and kidneys [ 20 – 24 ].…”

“…During open-heart surgery, levosimendan has been successfully used to treat preoperative and perioperative cardiac failure [ 7 , 8 ]. Levosimendan preconditioning prevented myocardial ischemic damage and inhibited cardiomyocyte apoptosis in ischemia-reperfusion (I/R) models [ 9 – 13 ]. Clinically, in addition to ischemia-reperfusion injury, a significantly high number of patients present with myocardial infarction (MI) due to prolonged acute coronary artery occlusion.…”

Therapeutic Targets for DOX-Induced Cardiomyopathy: Role of Apoptosis vs. Ferroptosis

“…A study examining the role of individual p38 isoforms, particularly the alternative isoforms p38γ and p38δ, in DOX-induced cardiotoxicity reported that p38δ plays an important role in promoting DOX-induced cardiotoxicity in females by inhibiting autophagy [37]. Conversely, many reports suggest that PI3k/Akt signaling, one of the most important kinases in the regulation of cell survival, has a significant effect on the inhibition of DOX-induced cardiotoxicity [38][39][40][41]. Indeed, the upregulation of the PI3k/Akt expression can inhibit apoptosis and improve DOX-induced cardiotoxicity [41][42][43].…”

The Effect of Levosimendan on Phosphine-Induced Nephrotoxicity: Biochemical and Histopathological Assessment

“…However, co-treatment of LEV showed a significant improvement in the activity of all three complexes in a dose-dependent manner. Based on the evidence, LEV can maintain mitochondrial function by improving respiration and modulation of mitochondrial calcium homeostasis 8 30 . Therefore, the present study's findings indicate that LEV can improve the renal tissue's complex activities and cellular energy supply in AlP-induced toxicity.…”