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).

Roles and Mechanisms of Interleukin-12 Family Members in Cardiovascular Diseases: Opportunities and Challenges

“…In an animal model of acute myocardial injury induced by the chemotherapeutic drug doxorubicin, deletion of IL-12p35 significantly increased cardiac injury, which was associated with increased inflammatory responses, oxidative stress, apoptosis, and autophagy. Treatment with recombinant mouse IL-12 significantly reversed these effects, suggesting that both IL-12 and IL-35 may play protective roles in cardiac injury induced by doxorubicin (Jia, 2018;Ye et al, 2018b;Ye et al, 2018c).…”

“…Induce and promote th17 differentiation IL-27 alone has no apparent stimulatory properties, collaboration with other ILs promote or inhibit T cell differentiation and proliferation Promote Treg activity, suppress the Teff cell (Th1, and Th17 ) activity Ma and Trinchieri, 2001;Kastelein et al, 2007;Collison and Vignali, 2008;Vignali et al, 2008;Cox et al, 2011;Vignali and Kuchroo, 2012;Wojno and Hunter, 2012;Sun et al, 2015 Regulation of inflammation Except inflammatory environment induced by DOX or Ang II, all play pro-inflammatory role Always play a proinflammatory roles, no anti-inflammatory effects had been reported Not only play an anti-inflammatory role, but also play a proinflammatory effects, may be associated with inflammatory microenvironment Always relieves the inflammatory response Davenport and Tipping, 2003;Vignali and Kuchroo, 2012;Jin et al, 2012;Koltsova et al, 2012;Li et al, 2012;Yan et al, 2012;Jääskeläinen et al, 2013;Abbas et al, 2015;Subramanian et al, 2015;Sun et al, 2015;Andrews et al, 2016;Tao et al, 2016;Hu et al, 2016;Gregersen et al, 2017;Fatkhullina et al, 2018;Ye et al, 2018b;Jia et al, 2019;Liu et al, 2019;Vargas-Alarcón et al, 2019;Ye et al, 2019 family members have significantly higher levels of expression in patients with atherosclerosis and coronary artery disease, and are closely related to the progression of these diseases.…”

Interleukin-35 pretreatment attenuates lipopolysaccharide-induced heart injury by inhibition of inflammation, apoptosis and fibrosis

“…IL-35 also inhibited lysophosphatidylcholine-induced mitochondrial reactive oxygen species (mtROS) production and human aortic endothelial activation (29,30). Furthermore, IL-35 was reported to exert anti-apoptotic effects that prevent diabetic neuropathic pain and doxorubicin-induced cardiac injury (24,31). Recently, Jia, et al (22) found that IL-35 reduced cardiac rupture, improved wound healing, and attenuated cardiac remodeling after myocardial infarction by promoting reparative CX3CR1 + Ly6C low macrophage survival.…”

“…This interaction induces signals within target cells that activate Janus kinase family members and phosphorylate members of this signal transduction pathway, which initiates the transcription of target genes to inhibit inflammatory responses (20,21). To date, IL-35 has been reported to participate in preventing myocardial infarction (22), Coxsackie virus-B3-induced viral myocarditis (23), and doxorubicin and angiotensin II-induced cardiac injury (24,25), implicating IL-35 as a promising therapeutic target for cardiovascular disease. However, the role of IL-35 in LPS-induced heart injury still remained obscure.…”

Exosomes Derived From Epigallocatechin Gallate-Treated Cardiomyocytes Attenuated Acute Myocardial Infarction by Modulating MicroRNA-30a

“…Apoptosis and autophagy are two types of gene-regulated cell death involved in heart disease (Ye et al, 2018). Yang Y et al showed that exosomal miR-30a was highly enriched in the serum of AMI patients, with increasing exosome release contributing to the restriction of autophagy (Yang et al, 2016).…”