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Klotho Improves Cardiac Function by Suppressing Reactive Oxygen Species (ROS) Mediated Apoptosis by Modulating
Huolan Zhu1, Yan Gao2, Shunming Zhu1
1Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, China (mainland).
Abstract:
BACKGROUND Anthracyclines-induced cardiotoxicity has become one of the major restrictions of their clinical applications. Klotho showed cardioprotective effects. This study aimed to investigate the effects and possible mechanisms of klotho on doxorubicin (DOX)-induced cardiotoxicity. MATERIAL AND METHODS Rats and isolated myocytes were exposed to DOX and treated with exogenous klotho. Specific inhibitors and siRNAs silencing MAPKs were also used to treat the animals and/or myocytes. An invasive hemodynamic method was used to determine cardiac functions. Intracellular ROS generation was evaluated by DHE staining. Western blotting was used to determine the phosphorylation levels of JNK, ERK, and p38 MAPKs in plasma extracts and Nrf2 in nuclear extracts. Nuclear translocation of Nrf2 in myocytes was evaluated by immunohistochemistry. Cell apoptosis was evaluated by TUNEL assay and flow cytometry. RESULTS Klotho treatment improved DOX-induced cardiac dysfunction in rats. The DOX-induced ROS accumulation and cardiac apoptosis were attenuated by klotho. Impaired phosphorylations of MAPKs, Nrf2 translocation and expression levels of HO1 and Prx1 were also attenuated by klotho treatment. However, the anti-oxidant and anti-apoptotic effects of klotho on DOX-exposed myocardium and myocytes were impaired by both specific inhibitors and siRNAs against MAPKs. Moreover, the recovery effects of klotho on phosphorylations of MAPKs, Nrf2 translocation and expression levels of HO1 and Prx1 were also impaired by specific inhibitors and siRNAs against MAPKs. CONCLUSIONS By recovering the activation of MAPKs signaling, klotho improved cardiac function loss which was triggered by DOX-induced ROS mediated cardiac apoptosis.
Insights
Klotho protects against doxorubicin-induced cardiotoxicity by activating MAPKs signaling, reducing oxidative stress and apoptosis. This finding offers a potential therapeutic strategy for anthracycline-induced heart damage.
Area of Science:
- Cardiology
- Molecular Biology
- Pharmacology
Background:
- Anthracyclines, like doxorubicin (DOX), are effective chemotherapeutics but cause significant cardiotoxicity, limiting their use.
- Klotho has demonstrated cardioprotective properties, suggesting a potential role in mitigating drug-induced heart damage.
Purpose of the Study:
- To investigate the protective effects of exogenous klotho against doxorubicin-induced cardiotoxicity.
- To elucidate the underlying mechanisms, focusing on the role of MAPKs and oxidative stress pathways.
Main Methods:
- Rats and isolated myocytes were exposed to doxorubicin and treated with klotho.
- Cardiac function was assessed using hemodynamic methods.
- Oxidative stress, apoptosis, MAPK phosphorylation, and Nrf2 pathway activation were evaluated using techniques including DHE staining, Western blotting, immunohistochemistry, TUNEL assay, and flow cytometry.
- MAPK inhibitors and siRNAs were employed to dissect signaling pathways.
Main Results:
- Klotho treatment significantly improved cardiac function in doxorubicin-treated rats.
- Klotho attenuated doxorubicin-induced reactive oxygen species (ROS) generation and cardiac apoptosis.
- Klotho treatment reversed impaired MAPK phosphorylation and enhanced Nrf2 translocation and expression of downstream targets HO1 and Prx1.
- Inhibition of MAPKs abolished the antioxidant and anti-apoptotic effects of klotho.
Conclusions:
- Klotho exerts cardioprotective effects against doxorubicin-induced cardiotoxicity.
- These effects are mediated through the recovery of MAPK signaling pathways, which in turn reduces ROS-mediated cardiac apoptosis.
