Lysosomal dysfunction and inflammatory sterol metabolism in pulmonary arterial hypertension

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2025-01-23 DOI:10.1126/science.adn7277

Lloyd D. Harvey, Mona Alotaibi, Yi-Yin Tai, Ying Tang, Hee-Jung J. Kim, Neil J. Kelly, Wei Sun, Chen-Shan C. Woodcock, Sanya Arshad, Miranda K. Culley, Wadih El Khoury, Rong Xie, Yassmin Al Aaraj, Jingsi Zhao, Neha Hafeez, Rashmi J. Rao, Siyi Jiang, Vinny Negi, Anna Kirillova, Dror Perk, Annie M. Watson, Claudette M. St. Croix, Donna B. Stolz, Ji Young Lee, Mary Hongying Cheng, Manling Zhang, Samuel Detmer, Edward Guzman, Rajith S. Manan, Rajan Saggar, Kathleen J. Haley, Aaron B. Waxman, Satoshi Okawa, Tae-Hwi Schwantes-An, Michael W. Pauciulo, Bing Wang, Amy Webb, Caroline Chauvet, Daniel G. Anderson, William C. Nichols, Ankit A. Desai, Robert Lafyatis, S. Mehdi Nouraie, Haodi Wu, Jeffrey G. McDonald, Susan Cheng, Ivet Bahar, Thomas Bertero, Raymond L. Benza, Mohit Jain, Stephen Y. Chan

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引用次数: 0

Abstract

Vascular inflammation regulates endothelial pathophenotypes, particularly in pulmonary arterial hypertension (PAH). Dysregulated lysosomal activity and cholesterol metabolism activate pathogenic inflammation, but their relevance to PAH is unclear. Nuclear receptor coactivator 7 ( NCOA7 ) deficiency in endothelium produced an oxysterol and bile acid signature through lysosomal dysregulation, promoting endothelial pathophenotypes. This oxysterol signature overlapped with a plasma metabolite signature associated with human PAH mortality. Mice deficient for endothelial Ncoa7 or exposed to an inflammatory bile acid developed worsened PAH. Genetic predisposition to NCOA7 deficiency was driven by single-nucleotide polymorphism rs11154337, which alters endothelial immunoactivation and is associated with human PAH mortality. An NCOA7-activating agent reversed endothelial immunoactivation and rodent PAH. Thus, we established a genetic and metabolic paradigm that links lysosomal biology and oxysterol processes to endothelial inflammation and PAH.

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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