气候变化领域集成服务门户(CCPortal): Type I interferon activation and endothelial dysfunction in caveolin-1 insufficiency-associated pulmonary arterial hypertension

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DOI	10.1073/pnas.2010206118
	Type I interferon activation and endothelial dysfunction in caveolin-1 insufficiency-associated pulmonary arterial hypertension
	Gairhe S.; Awad K.S.; Dougherty E.J.; Ferreyra G.A.; Wang S.; Yu Z.-X.; Takeda K.; Demirkale C.Y.; Torabi-Parizi P.; Austin E.D.; Elinoff J.M.; Danner R.L.
发表日期	2021
ISSN	00278424
卷号	118 期号:11
英文摘要	Interferonopathies, interferon (IFN)-α/β therapy, and caveolin-1 (CAV1) loss-of-function have all been associated with pulmonary arterial hypertension (PAH). Here, CAV1-silenced primary human pulmonary artery endothelial cells (PAECs) were proliferative and hypermigratory, with reduced cytoskeletal stress fibers. Signal transducers and activators of transcription (STAT) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) were both constitutively activated in these cells, resulting in a type I IFN-biased inflammatory signature. Cav1-/-mice that spontaneously develop pulmonary hypertension were found to have STAT1 and AKT activation in lung homogenates and increased circulating levels of CXCL10, a hallmark of IFN-mediated inflammation. PAH patients with CAV1 mutations also had elevated serum CXCL10 levels and their fibroblasts mirrored phenotypic and molecular features of CAV1-deficient PAECs. Moreover, immunofluorescence staining revealed endothelial CAV1 loss and STAT1 activation in the pulmonary arterioles of patients with idiopathic PAH, suggesting that this paradigm might not be limited to rare CAV1 frameshift mutations. While blocking JAK/STAT or AKT rescued aspects of CAV1 loss, only AKT inhibitors suppressed activation of both signaling pathways simultaneously. Silencing endothelial nitric oxide synthase (NOS3) prevented STAT1 and AKT activation induced by CAV1 loss, implicating CAV1/NOS3 uncoupling and NOS3 dysregulation in the inflammatory phenotype. Exogenous IFN reduced CAV1 expression, activated STAT1 and AKT, and altered the cytoskeleton of PAECs, implicating these mechanisms in PAH associated with autoimmune and autoinflammatory diseases, as well as IFN therapy. CAV1 insufficiency elicits an IFN inflammatory response that results in a dysfunctional endothelial cell phenotype and targeting this pathway may reduce pathologic vascular remodeling in PAH. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Caveolin-1; Inflammation; Interferon; Pulmonary arterial hypertension; Pulmonary artery endothelium
语种	英语
scopus关键词	caveolin 1; endothelial nitric oxide synthase; gamma interferon inducible protein 10; interferon; Janus kinase; phosphatidylinositol 3 kinase; protein kinase B; protein kinase B inhibitor; STAT protein; animal experiment; Article; autoimmune disease; autoinflammatory disease; cell migration; cell proliferation; controlled study; cytoskeleton; disease association; endothelial dysfunction; enzyme activation; fibroblast; frameshift mutation; human; human cell; immunofluorescence; inflammation; interferon induction; knockout mouse; lung arteriole; lung homogenate; mouse; nonhuman; phenotype; priority journal; protein blood level; protein deficiency; protein depletion; protein expression; pulmonary artery; pulmonary hypertension; stress fiber; vascular endothelial cell
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/180234
作者单位	Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, MD 20892, United States; Pathology Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20814, United States; Microscopy and Imaging Core Facility, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 20993, United States; Department of Pediatrics, School of Medicine, Vanderbilt University, Nashville, TN 37232, United States
推荐引用方式 GB/T 7714	Gairhe S.,Awad K.S.,Dougherty E.J.,et al. Type I interferon activation and endothelial dysfunction in caveolin-1 insufficiency-associated pulmonary arterial hypertension[J],2021,118(11).
APA	Gairhe S..,Awad K.S..,Dougherty E.J..,Ferreyra G.A..,Wang S..,...&Danner R.L..(2021).Type I interferon activation and endothelial dysfunction in caveolin-1 insufficiency-associated pulmonary arterial hypertension.Proceedings of the National Academy of Sciences of the United States of America,118(11).
MLA	Gairhe S.,et al."Type I interferon activation and endothelial dysfunction in caveolin-1 insufficiency-associated pulmonary arterial hypertension".Proceedings of the National Academy of Sciences of the United States of America 118.11(2021).