2. Academic Validation
  3. Protective effects of dimethyl itaconate in mice acute cardiotoxicity induced by doxorubicin

Protective effects of dimethyl itaconate in mice acute cardiotoxicity induced by doxorubicin

  • Biochem Biophys Res Commun. 2019 Sep 24;517(3):538-544. doi: 10.1016/j.bbrc.2019.07.046.
Qing Shan 1,  Xiaoyu Li 2,  Mei Zheng 3,  Xi Lin 4,  Guotao Lu 5,  Dongming Su 6,  Xiang Lu 7
Affiliations

Affiliations

  • 1 Department of Geriatrics, The Second Affilicated Hospital, Nanjing Medical University, Nanjing, 211166, People's Republic of China; Department of Geriatrics, Affilicated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, People's Republic of China.
  • 2 Department of Pathophysiology, Nanjing Medical University, Nanjing, 211166, People's Republic of China.
  • 3 Department of Cardiology, Beijing Jishuitan Hospital & the 4th Medical College of Peking University, Peking University, No. 31 Xinjiekou East Street, XiCheng District, Beijing, 100035, People's Republic of China.
  • 4 Department of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, People's Republic of China.
  • 5 Department of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, People's Republic of China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou, 225001, People's Republic of China.
  • 6 Center for Clinical Pathology and Laboratory, Affiliated Hospital of Yifu, Nanjing Medical University, Nanjing, 211166, People's Republic of China; Department of Pathoology, Nanjing Medical University, Nanjing, 211166, People's Republic of China. Electronic address: sudongming@njmu.edu.cn.
  • 7 Department of Geriatrics, The Second Affilicated Hospital, Nanjing Medical University, Nanjing, 211166, People's Republic of China. Electronic address: luxiang66@njmu.edu.cn.
PMID: 31376936 DOI: 10.1016/j.bbrc.2019.07.046
Abstract

Doxorubicin (DOX) is an antitumor drug widely used in hematological tumors and various solid tumors. However, the cardiotoxicity elicited by DOX severely limits its clinical treatment. Dimethyl itaconate (DI), a common form of itaconate, is found many potential targets for prevent heart injury. Here we employed wild type and Nrf2 knockout mice and induced a cardiotoxicity model by administration of DOX to clarify the effects of DI. After treatment with DI, we found that it could effectively alleviate the cardiotoxicity by analyzing morphology, LDH levels and heart weight/body weight ratio changes. Meanwhile we demonstrated that RIP3, a key protein of necrosis, was significantly decreased in DI treated group. Further we observed that treatment with DI could suppress oxidative stress by altering Nrf2/HO-1. Compared with vehicle group, DI could increase the tissue SOD and GSH, and reduce MDA levels, then DHE staining revealed that the level of ROS in DI group reduced by half. Finally, transmission electron microscope (TEM) data showed that treatment with DI obviously decreased the mitochondrial damage. While Nrf2 was ablated in mice, the protective effects of DI were vanished and SOD, GSH, MDA became unchanged related to vehicle group. This report provides the evidence for the protective effects of DI treatment in cardiotoxicity induced by DOX. On mechanisms, DI could reduce the oxidative stress by altering Nrf2/HO-1 pathway and prevent mitochondrial from damage. Taken together, these findings of this paper will afford the new therapeutic targets in DOX related cardiotoxicity.

Keywords

Acute cardiotoxicity; Dimethyl itaconate; Doxorubicin; Oxidative stress.

Figures
Products