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

被引：64

作者：

Ye, Jing ^{[1
,2
,4
,5
]}

Huang, Ying ^{[2
,3
]}

Que, Bin ^{[4
,5
]}

Chang, Chao ^{[6
]}

Liu, Wenjing ^{[6
]}

Hu, Haiying ^{[6
]}

Liu, Ling ^{[2
]}

Shi, Ying ^{[2
]}

Wang, Yuan ^{[1
]}

Wang, Menglong ^{[1
]}

Zeng, Tao ^{[2
]}

Zhen, Wang ^{[1
]}

Xu, Yao ^{[1
]}

Shi, Lei ^{[2
]}

Liu, Jianfang ^{[1
]}

Jiang, Huimin ^{[1
]}

Ye, Di ^{[1
]}

Lin, Yingzhong ^{[1
,2
]}

Wan, Jun ^{[1
]}

Ji, Qingwei ^{[4
,5
]}

机构：

[1] Wuhan Univ, Renmin Hosp, Cardiovasc Res Inst, Hubei Key Lab Cardiol,Dept Cardiol, Wuhan 430060, Hubei, Peoples R China

[2] Peoples Hosp Guangxi Zhuang Autonomous Reg, Dept Cardiol, Nanning, Peoples R China

[3] Peoples Hosp Guangxi Zhuang Autonomous Reg, Dept Ultrasound, Nanning 530021, Peoples R China

[4] Capital Med Univ, Beijing Anzhen Hosp, Emergency & Crit Care Ctr, Beijing 100029, Peoples R China

[5] Beijing Inst Heart Lung & Blood Vessel Dis, Beijing 100029, Peoples R China

[6] Handan First Hosp, Dept Cardiol, Handan 056002, Peoples R China

来源：

EBIOMEDICINE | 2018年 / 35卷

基金：

中国国家自然科学基金;

关键词：

Doxorubicin; 1L-12p35; knockout; Inflammation; Oxidative stress; Apoptosis; Autophagy; ANTHRACYCLINE-INDUCED CARDIOTOXICITY; REGULATORY T-CELLS; INDUCED CARDIOMYOPATHY; INDUCED ARTHRITIS; PROTECTS; IL-35; SUPPRESSION; DEFICIENCY; ACTIVATION; MECHANISMS;

D O I：

10.1016/j.ebiom.2018.06.009

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 apoptolic 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). (C) 2018 The Authors. Published by Elsevier B.V.

引用

页码：29 / 39

页数：11