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
Medical Scientist Training Program, University of Pittsburgh, Pittsburgh, PA, USA.
Center for Pulmonary Vascular Biology and Medicine, Pittsburgh, Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA.
Science. 2025 Jan 24;387(6732):eadn7277. doi: 10.1126/science.adn7277.
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 () 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 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.
血管炎症调节内皮病理表型，尤其是在肺动脉高压（PAH）中。溶酶体活性失调和胆固醇代谢激活致病性炎症，但其与PAH的相关性尚不清楚。内皮细胞中核受体辅激活因子7（）缺乏通过溶酶体失调产生氧化甾醇和胆汁酸特征，促进内皮病理表型。这种氧化甾醇特征与与人类PAH死亡率相关的血浆代谢物特征重叠。内皮细胞缺乏或暴露于炎性胆汁酸的小鼠PAH病情加重。NCOA7缺乏的遗传易感性由单核苷酸多态性rs11154337驱动，该多态性改变内皮免疫激活并与人类PAH死亡率相关。一种NCOA7激活剂可逆转内皮免疫激活和啮齿动物PAH。因此，我们建立了一种遗传和代谢模式，将溶酶体生物学和氧化甾醇过程与内皮炎症和PAH联系起来。
