Lysosomal dysfunction and inflammatory sterol metabolism in pulmonary arterial hypertension

• 成果类型: Article
• 署名作者: Harvey, Lloyd D.; Alotaibi, Mona; Tai, Yi-Yin; Tang, Ying; Kim, Hee-Jung J.; Kelly, Neil J.; Sun, Wei; Woodcock, Chen-Shan C.; Arshad, Sanya; Culley, Miranda K.; El Khoury, Wadih; Xie, Rong; Al Aaraj, Yassmin; Zhao, Jingsi; Hafeez, Neha; Rao, Rashmi J.; Jiang, Siyi; Negi, Vinny; Kirillova, Anna; Perk, Dror; Watson, Annie M.; St Croix, Claudette M.; Stolz, Donna B.; Lee, Ji Young; Cheng, Mary Hongying; Zhang, Manling; Detmer, Samuel; Guzman, Edward; Manan, Rajith S.; Saggar, Rajan; Haley, Kathleen J.; Waxman, Aaron B.; Okawa, Satoshi; Schwantes-An, Tae-Hwi; Pauciulo, Michael W.; Wang, Bing; Webb, Amy; Chauvet, Caroline; Anderson, Daniel G.; Nichols, William C.; Desai, Ankit A.; Lafyatis, Robert; Nouraie, S. Mehdi; Wu, Haodi; McDonald, Jeffrey G.; Cheng, Susan; Bahar, Ivet; Bertero, Thomas; Benza, Raymond L.; Jain, Mohit; Chan, Stephen Y.
• 署名单位: Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; University of California System; University of California San Diego; University of California System; University of California San Diego; University of California System; University of California San Diego; US Department of Veterans Affairs; Veterans Health Administration (VHA); VA Pittsburgh Healthcare System; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; State University of New York (SUNY) System; Stony Brook University; State University of New York (SUNY) System; Stony Brook University; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Harvard University; Massachusetts Institute of Technology (MIT); University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard Medical School; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Indiana University System; Indiana University Indianapolis; Indiana University System; Indiana University Indianapolis; Cincinnati Children's Hospital Medical Center; University System of Ohio; University of Cincinnati; University System of Ohio; Ohio State University; Universite Cote d'Azur; Centre National de la Recherche Scientifique (CNRS); Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; Cedars Sinai Medical Center; Icahn School of Medicine at Mount Sinai
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-10731
• DOI: 10.1126/science.adn7277
• 发表日期: 2025-01-24
• 页码: 376-+
• 关键词: endothelial-cells; 7-alpha-hydroxy-3-oxo-4-cholestenoic acid; tldc domain; bile-acids; cholesterol; pathogenesis; inhibition; DYNAMICS; exploration; deficiency

摘要

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.