研究人员发现，内皮细胞中核受体共激活因子7（NCOA7）缺乏通过溶酶体失调产生了氧固醇和胆汁酸标志，促进了内皮病理表型。这种氧固醇标志与与人类肺动脉高压（PAH）死亡率相关的血浆代谢物标志重叠。
内皮Ncoa7缺乏的老鼠，或暴露于炎症性胆汁酸的老鼠发展为加重的PAH。NCOA7缺乏的遗传易感性是由单核苷酸多态性rs11154337驱动的，这改变了内皮免疫激活并与人类PAH死亡率相关。一种激活NCOA7的药物，逆转了内皮免疫激活和啮齿类动物的PAH。
因此，研究人员建立了一个遗传和代谢范式，将溶酶体生物学和氧固醇过程与内皮炎症和PAH联系起来。
据悉，血管炎症调节内皮病理表型，尤其是在PAH中。溶酶体活性失调和胆固醇代谢紊乱激活致病性炎症，但它们与PAH的关系尚不明确。
附：英文原文
Title: Lysosomal dysfunction and inflammatory sterol metabolism in pulmonary arterial hypertension
Author: 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
Issue&Volume: 2025-01-24
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.
DOI: adn7277
Source: https://www.science.org/doi/10.1126/science.adn7277