1. Academic Validation
  2. Adiponectin agonist ADP355 ameliorates doxorubicin-induced cardiotoxicity by decreasing cardiomyocyte apoptosis and oxidative stress

Adiponectin agonist ADP355 ameliorates doxorubicin-induced cardiotoxicity by decreasing cardiomyocyte apoptosis and oxidative stress

  • Biochem Biophys Res Commun. 2020 Dec 10;533(3):304-312. doi: 10.1016/j.bbrc.2020.09.035.
Dan Zhao 1 Chao Xue 2 Jiaqi Li 2 Ke Feng 2 Peng Zeng 2 Yuanli Chen 3 Yajun Duan 3 Shuang Zhang 3 Xiaoju Li 2 Jihong Han 1 Xiaoxiao Yang 4
Affiliations

Affiliations

  • 1 College of Life Science, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China; Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
  • 2 College of Life Science, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China.
  • 3 Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
  • 4 Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China. Electronic address: yangxiaoxiao@hfut.edu.cn.
Abstract

Doxorubicin (DOX) is an anthracycline derivative and widely used as an Anticancer drug. However, the severe cardiotoxicity of DOX limits its application. ADP355 is an adiponectin-based active peptide with anti-liver fibrosis and atherosclerosis properties. It remains unclear the effects and involved mechanisms of ADP355 in DOX-induced cardiotoxicity. C57BL/6J mice were intraperitoneally injected DOX once a week to induce heart failure while receiving ADP355 treatment daily for 4 weeks. At the end of experiment, blood and heart tissues were collected. We found that ADP355 markedly improved DOX-induced cardiac dysfunction and histopathological damage, and decreased serum creatine kinase, Lactate Dehydrogenase and hydroxybutyrate dehydrogenase levels. The anti-apoptotic activity of ADP355 was indicated by reduction in TUNEL-positive cells and cleaved Caspase-3 expression, along with decreased BCL2-associated X protein/B cell lymphoma 2 (Bax/BCL2) levels in heart tissues. Additionally, ADP355 markedly increased DOX-decreased cell viability by reducing Bax/BCL2, but inhibited Reactive Oxygen Species production in H9c2 cells. Mechanistically, ADP355 attenuated expression of DOX-reduced nuclear factor-erythroid 2-related factor 2 (Nrf2) and superoxide dismutase 2, as well as mRNA levels of Nrf2 downstream targets. Furthermore, ADP355 activated Sirtuin 2 and its target genes. In conclusion, we demonstrate that ADP355 alleviates DOX-induced cardiotoxicity by inhibiting myocardial Apoptosis and oxidative stress through Nrf2 and Sirtuin 2 signaling pathways. These findings suggest that ADP355 can be a promising candidate for the treatment of cardiac dysfunction.

Keywords

ADP355; Apoptosis; Cardiotoxicity; Doxorubicin; Oxidative stress.

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