Genetic regulation and targeted reversal of lysosomal dysfunction and inflammatory sterol metabolism in pulmonary arterial hypertension
Year: 2024
Type: preprint
Abstract: Vascular inflammation critically regulates endothelial cell (EC) pathophenotypes, particularly in pulmonary arterial hypertension (PAH). Dysregulation of lysosomal activity and cholesterol metabolism have known inflammatory roles in disease, but their relevance to PAH is unclear. In human pulmonary arterial ECs and in PAH, we found that inflammatory cytokine induction of the nuclear receptor coactivator 7 (NCOA7) both preserved lysosomal acidification and served as a homeostatic brake to constrain EC immunoactivation. Conversely, NCOA7 deficiency promoted lysosomal dysfunction and proinflammatory oxysterol/bile acid generation that, in turn, contributed to EC pathophenotypes. In vivo, mice deficient for Ncoa7 or exposed to the inflammatory bile acid 7α-hydroxy-3-oxo-4-cholestenoic acid (7HOCA) displayed worsened PAH. Emphasizing this mechanism in human PAH, an unbiased, metabolome-wide association study (N=2,756) identified a plasma signature of the same NCOA7-dependent oxysterols/bile acids associated with PAH mortality (P<1.1x10-6). Supporting a genetic predisposition to NCOA7 deficiency, in genome-edited, stem cell-derived ECs, the common variant intronic SNP rs11154337 in NCOA7 regulated NCOA7 expression, lysosomal activity, oxysterol/bile acid production, and EC immunoactivation. Correspondingly, SNP rs11154337 was associated with PAH severity via six-minute walk distance and mortality in discovery (N=93, P=0.0250; HR=0.44, 95% CI [0.21-0.90]) and validation (N=630, P=2x10-4; HR=0.49, 95% CI [0.34-0.71]) cohorts. Finally, utilizing computational modeling of small molecule binding to NCOA7, we predicted and synthesized a novel activator of NCOA7 that prevented EC immunoactivation and reversed indices of rodent PAH. In summary, we have established a genetic and metabolic paradigm and a novel therapeutic agent that links lysosomal biology as well as oxysterol and bile acid processes to EC inflammation and PAH pathobiology. This paradigm carries broad implications for diagnostic and therapeutic development in PAH and in other conditions dependent upon acquired and innate immune regulation of vascular disease.
Authors: Lloyd D Harvey, Mona Alotaibi, Hee-Jung Janice Kim, Yi-Yin Tai, Ying Tang, Wei Sun, Wadih El Khoury, Chen-Shan C Woodcock, Yassmin Al Aaraj, Claudette M St. Croix, Donna B Stolz, Jiyoung Lee, Mary Hongying Cheng, Tae-Hwi Schwantes-An, Ankit A Desai, Michael W Pauciulo, William C Nichols, Amy Webb, Robert Lafyatis, Mehdi Nouraie, Haodi Wu, Jeffrey G McDonald, Caroline Chauvet, Susan Cheng, Ivet Bahar, Thomas Bertero, Raymond L Benza, Mohit Jain, Stephen Y Chan
Institutions: University of Pittsburgh, University of California San Diego, Stony Brook University, Indiana University Indianapolis, Cincinnati Children's Hospital Medical Center, University of Cincinnati, The Ohio State University, The University of Texas Southwestern Medical Center, Centre National de la Recherche Scientifique, Université Côte d'Azur, Institut de Pharmacologie Moléculaire et Cellulaire, Cedars-Sinai Medical Center, Cedars-Sinai Smidt Heart Institute, Icahn School of Medicine at Mount Sinai
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G108251326, G1441675580, G3968006953, G4656594441, G5486590446, G608324977, Understanding the dynamic of the vascular niche in pulmonary hypertension (PH). Matrix reprogramming forces PH., Defining the systems biology of the vascular matrix in pulmonary hypertension, To capitalize on activated adventitial fibroblasts metabolism to treat pulmonary hypertension, UBTD1: an ubiquitin scaffold protein at the cross roads of cell mechanics and cell metabolism, G9000030435, G9000037288, G9000124101, G9000130525, G9000195340, ACTN4 Binding to Functional SNP rs9277336 Controls the Genome Architecture and Endothelial Pathophenotypes in Pulmonary Arterial, Eicosanoid Pathways Underlying Disease Risk in Pulmonary Arterial Hypertension, Risk stratification in pulmonary arterial hypertension: Intersection of OMICs and longitudinal phenotypes through the PAH Biobank
OpenAlex ID: W4392388097