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Theranostics 2019; 9(16):4688-4703. doi:10.7150/thno.36862 This issue Cite

Research Paper

Absence of Interferon Regulatory Factor 1 Protects Against Atherosclerosis in Apolipoprotein E-Deficient Mice

Meng Du1,2, Xiaojing Wang3, Xiaoxiang Mao1,2, Liu Yang1,2, Kun Huang1,2, Fengxiao Zhang1,2, Yan Wang1,2, Xi Luo1,2, Cheng Wang1,2, Jiangtong Peng1,2, Minglu Liang2, Dan Huang1,2, Kai Huang1,2✉

1. Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
2. Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
3. Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

✉ Corresponding author: Kai Huang, MD, PhD, Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. Address: 1277 Jiefang Ave., Wuhan, China, 430000. Tel/Fax: 86-27-85726650; E-mail: unionhuangcom; d201378184edu.cn More

Citation:
Du M, Wang X, Mao X, Yang L, Huang K, Zhang F, Wang Y, Luo X, Wang C, Peng J, Liang M, Huang D, Huang K. Absence of Interferon Regulatory Factor 1 Protects Against Atherosclerosis in Apolipoprotein E-Deficient Mice. Theranostics 2019; 9(16):4688-4703. doi:10.7150/thno.36862. https://www.thno.org/v09p4688.htm
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Abstract

Graphic abstract

Deciphering the molecular and cellular processes involved in foam cell formation is critical to understanding the pathogenesis of atherosclerosis. Interferon regulatory factor 1 (IRF1) was first identified as a transcriptional regulator of type-I interferons (IFNs) and IFN inducible genes. Our study aims to explore the role of IRF1 in atherosclerotic foam cell formation and understand the functional diversity of IRF1 in various cell types contributing to atherosclerosis.

Methods: We induced experimental atherosclerosis in ApoE-/-IRF1-/- mice and evaluated the effect of IRF1 on disease progression and foam cell formation.

Results: IRF1 expression was increased in human and mouse atherosclerotic lesions. IRF1 deficiency inhibited modified lipoprotein uptake and promoted cholesterol efflux, along with altered expression of genes implicated in lipid metabolism. Gene expression analysis identified scavenger receptor (SR)-AI as a regulated target of IRF1, and SR-AI silencing completely abrogated the increased uptake of modified lipoprotein induced by IRF1. Our data also explain a mechanism underlying endotoxemia-complicated atherogenesis as follows: two likely pro-inflammatory agents, oxidized low-density lipoprotein (ox-LDL) and bacterial lipopolysaccharide (LPS), exert cooperative effects on foam cell formation, which is partly attributable to a shift of IRF1-Ubc9 complex to IRF1- myeloid differentiation primary response protein 88 (Myd88) complex and subsequent IRF1 nuclear translocation. Additionally, it seems that improved function of vascular smooth muscle cells (VSMCs) also accounts for the diminished and more stable atherosclerotic plaques observed in ApoE-/-IRF1-/- mice.

Conclusions: Our findings demonstrate an unanticipated role of IRF1 in the regulation of gene expression implicated in foam cell formation and identify IRF1 activation as a new risk factor in the development, progression and instability of atherosclerotic lesions.

Keywords: IRF1, atherosclerosis, plaque stability, foam cell formation, endotoxemia

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APA
Du, M., Wang, X., Mao, X., Yang, L., Huang, K., Zhang, F., Wang, Y., Luo, X., Wang, C., Peng, J., Liang, M., Huang, D., Huang, K. (2019). Absence of Interferon Regulatory Factor 1 Protects Against Atherosclerosis in Apolipoprotein E-Deficient Mice. Theranostics, 9(16), 4688-4703. https://doi.org/10.7150/thno.36862.

ACS
Du, M.; Wang, X.; Mao, X.; Yang, L.; Huang, K.; Zhang, F.; Wang, Y.; Luo, X.; Wang, C.; Peng, J.; Liang, M.; Huang, D.; Huang, K. Absence of Interferon Regulatory Factor 1 Protects Against Atherosclerosis in Apolipoprotein E-Deficient Mice. Theranostics 2019, 9 (16), 4688-4703. DOI: 10.7150/thno.36862.

NLM
Du M, Wang X, Mao X, Yang L, Huang K, Zhang F, Wang Y, Luo X, Wang C, Peng J, Liang M, Huang D, Huang K. Absence of Interferon Regulatory Factor 1 Protects Against Atherosclerosis in Apolipoprotein E-Deficient Mice. Theranostics 2019; 9(16):4688-4703. doi:10.7150/thno.36862. https://www.thno.org/v09p4688.htm

CSE
Du M, Wang X, Mao X, Yang L, Huang K, Zhang F, Wang Y, Luo X, Wang C, Peng J, Liang M, Huang D, Huang K. 2019. Absence of Interferon Regulatory Factor 1 Protects Against Atherosclerosis in Apolipoprotein E-Deficient Mice. Theranostics. 9(16):4688-4703.

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