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

Xin Gu; Lin Zhao; Jiabao Ye; Lin Chen; Chenyan Sui; Baihong Li; Xiaoyan Wang; Jun Zhang; Yingqiang Du

doi:10.3892/etm.2023.12112

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

Exp Ther Med. 2023 Jul 11;26(3):413. doi: 10.3892/etm.2023.12112. eCollection 2023 Sep.

Authors

Xin Gu¹, Lin Zhao¹, Jiabao Ye², Lin Chen², Chenyan Sui³, Baihong Li¹, Xiaoyan Wang¹, Jun Zhang², Yingqiang Du²

Affiliations

¹ Department of Cardiology, The Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, P.R. China.
² 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.
³ Department of Neurology, The Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, P.R. China.

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.

Keywords: 1; 25(OH)2D3; cardiomyopathy; doxorubicin; nod-like receptor family pyrin domain-containing 3 inflammasome; oxidative stress.

Grants and funding

Funding: The present study was supported by the Natural Science Foundation of Jiangsu Province (grant no. BK20210101), the Scientific Research Project of Gusu Health Talent Plan (grant no. GSWS2022067), the General Project of Suzhou Science and Technology Administration (grant no. SKYD2022131), the Research Project of Gusu School of Nanjing Medical University (grant no. GSKY20210214), the Key Project of Jiangsu Provincial Health Commission (grant no. ZDA2020023), the General Project of Wuxi Traditional Chinese Medicine Administration (grant no. ZYKJ202013) and the General Project of Wuxi Science and Technology Administration (grant no. N20202019).