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

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.

• Authors: Dan Zhao, Chao Xue, Jiaqi Li, Ke Feng, Peng Zeng, Yuanli Chen, Yajun Duan, Shuang Zhang, Xiaoju Li, Jihong Han, Xiaoxiao Yang
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 533 Issue 3 Pg. 304-312 (12 10 2020) ISSN: 1090-2104 [Electronic] United States
• PMID: 32958254 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Adiponectin
• Adipoq protein, mouse
• Antibiotics, Antineoplastic
• Bax protein, mouse
• Cardiotonic Agents
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• Oligopeptides
• Proto-Oncogene Proteins c-bcl-2
• Reactive Oxygen Species
• asparaginyl-isoleucyl-prolyl-norvalyl-leucyl-tyrosyl-seryl-phenylalanyl-alanyl-serinamide
• bcl-2-Associated X Protein
• Bcl2 protein, mouse
• Doxorubicin
• Superoxide Dismutase
• superoxide dismutase 2
• Casp3 protein, mouse
• Caspase 3
• Sirt2 protein, mouse
• Sirtuin 2

Topics

• Adiponectin (agonists, genetics, metabolism)
• Animals
• Antibiotics, Antineoplastic (toxicity)
• Apoptosis (drug effects)
• Cardiotonic Agents (pharmacology)
• Cardiotoxicity (drug therapy, etiology, genetics, metabolism)
• Caspase 3 (genetics, metabolism)
• Cell Line
• Doxorubicin (antagonists & inhibitors, toxicity)
• Gene Expression Regulation
• Heart Failure (chemically induced, genetics, metabolism, prevention & control)
• Male
• Mice
• Mice, Inbred C57BL
• Myocardium (metabolism, pathology)
• Myocytes, Cardiac (drug effects, metabolism, pathology)
• NF-E2-Related Factor 2 (genetics, metabolism)
• Oligopeptides (pharmacology)
• Oxidative Stress
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Reactive Oxygen Species (antagonists & inhibitors, metabolism)
• Signal Transduction
• Sirtuin 2 (genetics, metabolism)
• Superoxide Dismutase (genetics, metabolism)
• bcl-2-Associated X Protein (genetics, metabolism)