Interleukin-12p35 Knock Out Aggravates Doxorubicin-Induced Cardiac Injury and Dysfunction by Aggravating the Inflammatory Response, Oxidative Stress, Apoptosis and Autophagy in Mice.

Abstract

BACKGROUND:

Recent evidence has demonstrated that interleukin 12p35 knockout (IL-12p35 KO) is involved in cardiac diseases by regulating the inflammatory response. The involvement of inflammatory cells has also been observed in doxorubicin (DOX)-induced cardiac injury. This study aimed to investigate whether IL-12p35 KO affects DOX-induced cardiac injury and the underlying mechanisms.

METHODS:

First, the effect of DOX treatment on cardiac IL-12p35 expression was assessed. In addition, to investigate the effect of IL-12p35 KO on DOX-induced cardiac injury, IL-12p35 KO mice were treated with DOX. Because IL-12p35 is the mutual subunit of IL-12 and IL-35, to determine the cytokine that mediates the effect of IL-12p35 KO on DOX-induced cardiac injury, mice were given phosphate-buffered saline (PBS), mouse recombinant IL-12 (rIL-12) or rIL-35 before treatment with DOX.

RESULTS:

DOX treatment significantly increased the level of cardiac IL-12p35 expression. In addition, IL-12p35 KO mice exhibited higher serum and heart lactate dehydrogenase levels, higher serum and heart creatine kinase myocardial bound levels, and greater cardiac dysfunction than DOX-treated mice. Furthermore, IL-12p35 KO further increased M1 macrophage and decreased M2 macrophage differentiation, aggravated the imbalance of oxidants and antioxidants, and further activated the mitochondrial apoptotic pathway and endoplasmic reticulum stress autophagy pathway. Both rIL-12 and rIL-35 protected against DOX-induced cardiac injury by alleviating the inflammatory response, oxidative stress, apoptosis and autophagy.

CONCLUSIONS:

IL-12p35 KO aggravated DOX-induced cardiac injury by amplifying the levels of inflammation, oxidative stress, apoptosis and autophagy. (234 words).

• Authors: Jing Ye, Ying Huang, Bin Que, Chao Chang, Wenjing Liu, Haiying Hu, Ling Liu, Ying Shi, Yuan Wang, Menglong Wang, Tao Zeng, Wang Zhen, Yao Xu, Lei Shi, Jianfang Liu, Huimin Jiang, Di Ye, Yingzhong Lin, Jun Wan, Qingwei Ji
• Journal: EBioMedicine (EBioMedicine) Vol. 35 Pg. 29-39 (Sep 2018) ISSN: 2352-3964 [Electronic] Netherlands
• PMID: 30228093 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Biomarkers
• Cardiotonic Agents
• Interleukin-12 Subunit p35
• STAT3 Transcription Factor
• Doxorubicin

Topics

• Animals
• Apoptosis (drug effects)
• Autophagosomes (metabolism, ultrastructure)
• Autophagy (drug effects)
• Biomarkers (metabolism)
• Cardiotonic Agents (metabolism)
• Cardiovascular Diseases (chemically induced, diagnostic imaging, pathology, physiopathology)
• Doxorubicin (adverse effects)
• Endoplasmic Reticulum Stress (drug effects)
• Hemodynamics (drug effects)
• Inflammation (pathology)
• Interleukin-12 Subunit p35 (deficiency, metabolism)
• Macrophages (metabolism)
• Mice, Inbred C57BL
• Mice, Knockout
• Myocardium (pathology, ultrastructure)
• Oxidative Stress (drug effects)
• Phosphorylation (drug effects)
• STAT3 Transcription Factor (metabolism)