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DOI	10.1073/pnas.2023899118
	Aryl hydrocarbon receptor is essential for the pathogenesis of pulmonary arterial hypertension
	Masaki T.; Okazawa M.; Asano R.; Inagaki T.; Ishibashi T.; Yamagishi A.; Umeki-Mizushima S.; Nishimura M.; Manabe Y.; Ishibashi-Ueda H.; Shirai M.; Tsuchimochi H.; Pearson J.T.; Kumanogoh A.; Sakata Y.; Ogo T.; Kishimoto T.; Nakaoka Y.
发表日期	2021
ISSN	00278424
卷号	118 期号:11
英文摘要	Pulmonary arterial hypertension (PAH) is a devastating disease characterized by arteriopathy in the small to medium-sized distal pulmonary arteries, often accompanied by infiltration of inflammatory cells. Aryl hydrocarbon receptor (AHR), a nuclear receptor/ transcription factor, detoxifies xenobiotics and regulates the differentiation and function of various immune cells. However, the role of AHR in the pathogenesis of PAH is largely unknown. Here, we explore the role of AHR in the pathogenesis of PAH. AHR agonistic activity in serum was significantly higher in PAH patients than in healthy volunteers and was associated with poor prognosis of PAH. Sprague-Dawley rats treated with the potent endogenous AHR agonist, 6-formylindolo[3,2-b]carbazole, in combination with hypoxia develop severe pulmonary hypertension (PH) with plexiform-like lesions, whereas Sprague-Dawley rats treated with the potent vascular endothelial growth factor receptor 2 inhibitors did not. Ahr-knockout (Ahr-/-) rats generated using the CRISPR/ Cas9 system did not develop PH in the SU5416/hypoxia model. A diet containing Qing-Dai, a Chinese herbal drug, in combination with hypoxia led to development of PH in Ahr+/+rats, but not in Ahr-/-rats. RNA-seq analysis, chromatin immunoprecipitation (ChIP)-seq analysis, immunohistochemical analysis, and bone marrow transplantation experiments show that activation of several inflammatory signaling pathways was up-regulated in endothelial cells and peripheral blood mononuclear cells, which led to infiltration of CD4+IL-21+T cells and MRC1+macrophages into vascular lesions in an AHR-dependent manner. Taken together, AHR plays crucial roles in the development and progression of PAH, and the AHR-signaling pathway represents a promising therapeutic target for PAH. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Aryl hydrocarbon receptor (AHR); Inflammation; Pulmonary arterial hypertension; Qing-Dai; Transcription factor
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180282
作者单位	Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, 564-8565, Japan; Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, 565-0871, Japan; Department of Advanced Medical Research for Pulmonary Hypertension, National Cerebral and Cardiovascular Center, Suita, 564-8565, Japan; Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, 564-8565, Japan; Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, 565-0871, Japan; Department of Pathology, National Cerebral and Cardiovascular Center, Suita, 564-8565, Japan; Omics Research Center, National Cerebral and Cardiovascular Center, Suita, 564-8565, Japan; Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, 564-8565, Japan; Department of Immune Regulation, Immunology Frontier Research Center, Osaka University, Suita, 565-0871, ...
推荐引用方式 GB/T 7714	Masaki T.,Okazawa M.,Asano R.,et al. Aryl hydrocarbon receptor is essential for the pathogenesis of pulmonary arterial hypertension[J],2021,118(11).
APA	Masaki T..,Okazawa M..,Asano R..,Inagaki T..,Ishibashi T..,...&Nakaoka Y..(2021).Aryl hydrocarbon receptor is essential for the pathogenesis of pulmonary arterial hypertension.Proceedings of the National Academy of Sciences of the United States of America,118(11).
MLA	Masaki T.,et al."Aryl hydrocarbon receptor is essential for the pathogenesis of pulmonary arterial hypertension".Proceedings of the National Academy of Sciences of the United States of America 118.11(2021).