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

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)(2)D-3 has antioxidant and anti-inflammatory effects and can inhibit the renin-angiotensin system. However, the effects of 1,25(OH)(2)D-3 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)(2)D-3. 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)(2)D-3 on histone modification in the NLRP3 and Nrf2 promoters. The results showed that 1,25(OH)(2)D-3 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)(2)D-3 treatment. In addition, 1,25(OH)(2)D-3 was found to inhibit the NLRP3 inflammasome and KEAP-Nrf2 pathways through regulation of the levels of H3K4me(3), H3K27me(3) and H2AK119Ub in the NLRP3 and Nrf2 promoters. In conclusion, the present study demonstrated that 1,25(OH)(2)D-3 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)(2)D-3 may be a potential drug candidate for the treatment of DOX-induced cardiomyopathy.