Lysosomal dysfunction and inflammatory sterol metabolism in pulmonary arterial hypertension.

Journal: Science (New York, N.Y.)
Published:
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.

Authors
Lloyd Harvey, Mona Alotaibi, Yi-yin Tai, Ying Tang, Hee-jung Kim, Neil Kelly, Wei Sun, Chen-shan Woodcock, Sanya Arshad, Miranda Culley, Wadih El Khoury, Rong Xie, Yassmin Al Aaraj, Jingsi Zhao, Neha Hafeez, Rashmi Rao, Siyi Jiang, Vinny Negi, Anna Kirillova, Dror Perk, Annie Watson, Claudette St Croix, Donna Stolz, Ji Lee, Mary Cheng, Manling Zhang, Samuel Detmer, Edward Guzman, Rajith Manan, Rajan Saggar, Kathleen Haley, Aaron Waxman, Satoshi Okawa, Tae-hwi Schwantes An, Michael Pauciulo, Bing Wang, Amy Webb, Caroline Chauvet, Daniel Anderson, William Nichols, Ankit Desai, Robert Lafyatis, S Nouraie, Haodi Wu, Jeffrey Mcdonald, Susan Cheng, Ivet Bahar, Thomas Bertero, Raymond Benza, Mohit Jain, Stephen Chan
Relevant Conditions

Hypertension