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New insight for SS‑31 in treating diabetic cardiomyopathy: Activation of mitoGPX4 and alleviation of mitochondria‑dependent ferroptosis

  • Authors:
    • Lie Xiong
    • Huilin Hu
    • Fuxiang Zhu
    • Hanqiang Shi
    • Xiaoliang Fan
    • Sunfeng Pan
    • Feiye Zhu
    • Junyong Zhang
    • Zhongwei Yu
    • Yanbo Shi
  • View Affiliations / Copyright

    Affiliations: Central Laboratory of Molecular Medicine Center, Zhejiang Chinese Medical University Affiliated Jiaxing Traditional Chinese Medicine Hospital, Jiaxing, Zhejiang 314000, P.R. China, Department of Cardiology, Zhejiang Chinese Medical University Affiliated Jiaxing Traditional Chinese Medicine Hospital, Jiaxing, Zhejiang 314000, P.R. China, Jiaxing Key Laboratory of Diabetic Angiopathy Research, Jiaxing, Zhejiang 314000, P.R. China, Central Laboratory of Molecular Medicine Center, Zhejiang Chinese Medical University Affiliated Jiaxing Traditional Chinese Medicine Hospital, Jiaxing, Zhejiang 314000, P.R. China, Department of Clinical Pharmacy, Zhejiang Chinese Medical University Affiliated Jiaxing Traditional Chinese Medicine Hospital, Jiaxing, Zhejiang 314000, P.R. China, Jiaxing Key Laboratory of Diabetic Angiopathy Research, Jiaxing, Zhejiang 314000, P.R. China, Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China, College of Biological, Chemical Sciences and Engineering, Jiaxing University, Jiaxing, Zhejiang 314001, P.R. China
    Copyright: © Xiong et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 112
    |
    Published online on: October 4, 2024
       https://doi.org/10.3892/ijmm.2024.5436
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Abstract

SS‑31 is a mitochondria‑targeting antioxidant that exhibits promising therapeutic potential for various diseases; however, its protective effect on diabetic cardiomyopathy (DCM) remains to be elucidated. At present, SS‑31 is considered not only to mitigate cardiolipin oxidative damage, but also to alleviate ferroptosis. The present study aimed to explore SS‑31 as a potential therapeutic strategy for improving DCM by alleviating mitochondria‑dependent ferroptosis. In vitro, H9C2 cells were exposed to 35 mM glucose for 24 h to induce high glucose damage, then were simultaneously treated with 10, 20 or 50 µM SS‑31. In addition, in vivo studies were conducted on diabeticC57BL/6J mice, which were induced to develop DCM over 4 weeks, followed by intraperitoneal injections with 2.5 mg/kg/day SS‑31 for a further 4 weeks. The elevation of serum lactate dehydrogenase and creatine kinase isoenzymes, the reduction of fractional shortening and ejection fraction, the rupture of myocardial fibers and the deposition of collagen indicated the establishment of the DCM mouse model. The results of the present study indicated that SS‑31 effectively alleviated these pathological changes and exhibited significant efficacy in ameliorating mitochondrial dysfunction, such as by promoting adenosine triphosphate generation, improving mitochondrial membrane potential and restoring the mitochondrial ultrastructure. Further experiments suggested that activation of the mitochondrial glutathione (mitoGSH)/mitochondrial glutathione peroxidase 4 (mitoGPX4) pathway and the elimination of mitochondrial ferrous ions may constitute the mechanisms by which SS‑31 treats DCM. Therefore, the present study revealed that mitochondria‑dependent ferroptosis could serve as a pathogenic mechanism of DCM and highlighted that the cardioprotective effects of SS‑31 against DCM involves activation of the mitoGSH/mitoGPX4 pathway. Due to the safety profile and cardiac protective effects of SS‑31, SS‑31 was considered a promising strategy for treating DCM.
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Copy and paste a formatted citation
Spandidos Publications style
Xiong L, Hu H, Zhu F, Shi H, Fan X, Pan S, Zhu F, Zhang J, Yu Z, Shi Y, Shi Y, et al: New insight for SS‑31 in treating diabetic cardiomyopathy: Activation of mitoGPX4 and alleviation of mitochondria‑dependent ferroptosis. Int J Mol Med 54: 112, 2024.
APA
Xiong, L., Hu, H., Zhu, F., Shi, H., Fan, X., Pan, S. ... Shi, Y. (2024). New insight for SS‑31 in treating diabetic cardiomyopathy: Activation of mitoGPX4 and alleviation of mitochondria‑dependent ferroptosis. International Journal of Molecular Medicine, 54, 112. https://doi.org/10.3892/ijmm.2024.5436
MLA
Xiong, L., Hu, H., Zhu, F., Shi, H., Fan, X., Pan, S., Zhu, F., Zhang, J., Yu, Z., Shi, Y."New insight for SS‑31 in treating diabetic cardiomyopathy: Activation of mitoGPX4 and alleviation of mitochondria‑dependent ferroptosis". International Journal of Molecular Medicine 54.6 (2024): 112.
Chicago
Xiong, L., Hu, H., Zhu, F., Shi, H., Fan, X., Pan, S., Zhu, F., Zhang, J., Yu, Z., Shi, Y."New insight for SS‑31 in treating diabetic cardiomyopathy: Activation of mitoGPX4 and alleviation of mitochondria‑dependent ferroptosis". International Journal of Molecular Medicine 54, no. 6 (2024): 112. https://doi.org/10.3892/ijmm.2024.5436
Copy and paste a formatted citation
x
Spandidos Publications style
Xiong L, Hu H, Zhu F, Shi H, Fan X, Pan S, Zhu F, Zhang J, Yu Z, Shi Y, Shi Y, et al: New insight for SS‑31 in treating diabetic cardiomyopathy: Activation of mitoGPX4 and alleviation of mitochondria‑dependent ferroptosis. Int J Mol Med 54: 112, 2024.
APA
Xiong, L., Hu, H., Zhu, F., Shi, H., Fan, X., Pan, S. ... Shi, Y. (2024). New insight for SS‑31 in treating diabetic cardiomyopathy: Activation of mitoGPX4 and alleviation of mitochondria‑dependent ferroptosis. International Journal of Molecular Medicine, 54, 112. https://doi.org/10.3892/ijmm.2024.5436
MLA
Xiong, L., Hu, H., Zhu, F., Shi, H., Fan, X., Pan, S., Zhu, F., Zhang, J., Yu, Z., Shi, Y."New insight for SS‑31 in treating diabetic cardiomyopathy: Activation of mitoGPX4 and alleviation of mitochondria‑dependent ferroptosis". International Journal of Molecular Medicine 54.6 (2024): 112.
Chicago
Xiong, L., Hu, H., Zhu, F., Shi, H., Fan, X., Pan, S., Zhu, F., Zhang, J., Yu, Z., Shi, Y."New insight for SS‑31 in treating diabetic cardiomyopathy: Activation of mitoGPX4 and alleviation of mitochondria‑dependent ferroptosis". International Journal of Molecular Medicine 54, no. 6 (2024): 112. https://doi.org/10.3892/ijmm.2024.5436
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