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1,25(OH)2D3 ameliorates doxorubicin‑induced cardiomyopathy by inhibiting the NLRP3 inflammasome and oxidative stress

  • Authors:
    • Xin Gu
    • Lin Zhao
    • Jiabao Ye
    • Lin Chen
    • Chenyan Sui
    • Baihong Li
    • Xiaoyan Wang
    • Jun Zhang
    • Yingqiang Du
  • View Affiliations / Copyright

    Affiliations: Department of Cardiology, The Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, P.R. China, Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu 215008, P.R. China, Department of Neurology, The Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, P.R. China
    Copyright: © Gu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 413
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    Published online on: July 11, 2023
       https://doi.org/10.3892/etm.2023.12112
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Abstract

Doxorubicin (DOX), as a chemotherapy agent with marked therapeutic effect, can be used to treat certain types of cancer such as leukemia, lymphoma and breast cancer. However, the toxic effects of DOX on cardiomyocytes limit its clinical application. Oxidative stress has been documented to serve a pivotal role in DOX‑induced cardiomyopathy. Previous studies have reported that 1,25(OH)2D3 has antioxidant and anti‑inflammatory effects and can inhibit the renin‑angiotensin system. However, the effects of 1,25(OH)2D3 on the pathophysiological processes of DOX‑induced cardiomyopathy and its mechanisms remain poorly understood. To investigate these potential effects, C57BL/6J mice were used to construct a DOX‑induced cardiomyopathy model and treated with 1,25(OH)2D3. At 4 weeks after the first injection of DOX, cardiac function and myocardial injury were evaluated by echocardiograph and ELISA. Masson's trichrome staining and RT‑qPCR were used to assess myocardial fibrosis, and immunohistochemistry and western blotting were performed to analyze expression levels of inflammation and oxidative stress, and the NLRP3 inflammasome pathway. ChIP assay was used to assess the effects of 1,25(OH)2D3 on histone modification in the NLRP3 and Nrf2 promoters. The results showed that 1,25(OH)2D3 treatment increased LVEF and LVFS, reduced serum levels of BNP and cTnT, inhibited the collagen deposition and profibrotic molecular expression, and downregulated the levels of inflammatory cytokines in DOX‑induced cardiomyopathy. ROS and antioxidant indices were also ameliorated after 1,25(OH)2D3 treatment. In addition, 1,25(OH)2D3 was found to inhibit the NLRP3 inflammasome and KEAP‑Nrf2 pathways through regulation of the levels of H3K4me3, H3K27me3 and H2AK119Ub in the NLRP3 and Nrf2 promoters. In conclusion, the present study demonstrated that 1,25(OH)2D3 regulated histone modification in the NLRP3 and Nrf2 promoters, which in turn inhibits the activation of NLRP3 inflammasome and oxidative stress in cardiomyocytes, alleviating DOX‑induced cardiomyopathy. Therefore, 1,25(OH)2D3 may be a potential drug candidate for the treatment of DOX‑induced cardiomyopathy.
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Copy and paste a formatted citation
Spandidos Publications style
Gu X, Zhao L, Ye J, Chen L, Sui C, Li B, Wang X, Zhang J and Du Y: 1,25(OH)<sub>2</sub>D<sub>3</sub> ameliorates doxorubicin‑induced cardiomyopathy by inhibiting the NLRP3 inflammasome and oxidative stress. Exp Ther Med 26: 413, 2023.
APA
Gu, X., Zhao, L., Ye, J., Chen, L., Sui, C., Li, B. ... Du, Y. (2023). 1,25(OH)<sub>2</sub>D<sub>3</sub> ameliorates doxorubicin‑induced cardiomyopathy by inhibiting the NLRP3 inflammasome and oxidative stress. Experimental and Therapeutic Medicine, 26, 413. https://doi.org/10.3892/etm.2023.12112
MLA
Gu, X., Zhao, L., Ye, J., Chen, L., Sui, C., Li, B., Wang, X., Zhang, J., Du, Y."1,25(OH)<sub>2</sub>D<sub>3</sub> ameliorates doxorubicin‑induced cardiomyopathy by inhibiting the NLRP3 inflammasome and oxidative stress". Experimental and Therapeutic Medicine 26.3 (2023): 413.
Chicago
Gu, X., Zhao, L., Ye, J., Chen, L., Sui, C., Li, B., Wang, X., Zhang, J., Du, Y."1,25(OH)<sub>2</sub>D<sub>3</sub> ameliorates doxorubicin‑induced cardiomyopathy by inhibiting the NLRP3 inflammasome and oxidative stress". Experimental and Therapeutic Medicine 26, no. 3 (2023): 413. https://doi.org/10.3892/etm.2023.12112
Copy and paste a formatted citation
x
Spandidos Publications style
Gu X, Zhao L, Ye J, Chen L, Sui C, Li B, Wang X, Zhang J and Du Y: 1,25(OH)<sub>2</sub>D<sub>3</sub> ameliorates doxorubicin‑induced cardiomyopathy by inhibiting the NLRP3 inflammasome and oxidative stress. Exp Ther Med 26: 413, 2023.
APA
Gu, X., Zhao, L., Ye, J., Chen, L., Sui, C., Li, B. ... Du, Y. (2023). 1,25(OH)<sub>2</sub>D<sub>3</sub> ameliorates doxorubicin‑induced cardiomyopathy by inhibiting the NLRP3 inflammasome and oxidative stress. Experimental and Therapeutic Medicine, 26, 413. https://doi.org/10.3892/etm.2023.12112
MLA
Gu, X., Zhao, L., Ye, J., Chen, L., Sui, C., Li, B., Wang, X., Zhang, J., Du, Y."1,25(OH)<sub>2</sub>D<sub>3</sub> ameliorates doxorubicin‑induced cardiomyopathy by inhibiting the NLRP3 inflammasome and oxidative stress". Experimental and Therapeutic Medicine 26.3 (2023): 413.
Chicago
Gu, X., Zhao, L., Ye, J., Chen, L., Sui, C., Li, B., Wang, X., Zhang, J., Du, Y."1,25(OH)<sub>2</sub>D<sub>3</sub> ameliorates doxorubicin‑induced cardiomyopathy by inhibiting the NLRP3 inflammasome and oxidative stress". Experimental and Therapeutic Medicine 26, no. 3 (2023): 413. https://doi.org/10.3892/etm.2023.12112
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