Genetic regulation and targeted reversal of lysosomal dysfunction and inflammatory sterol metabolism in pulmonary arterial hypertension
Rattachement africain : us, fr. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
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.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Genetic regulation and targeted reversal of lysosomal dysfunction and inflammatory sterol metabolism in pulmonary arterial hypertension
- Date Crossref
- 01/03/2024
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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University of Pittsburgh and Blood Vascular Medicine Institute pays non établi dans la noticeUniversité ou école supérieure
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University of Pittsburgh Medical Center pays non établi dans la noticeÉtablissement de santé
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University of California System pays non établi dans la noticeUniversité ou école supérieure
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University of California San Diego Departments of Medicine and Pharmacology pays non établi dans la noticeUniversité ou école supérieure
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Stony Brook University Department of Biochemistry and Cell Biology pays non établi dans la noticeUniversité ou école supérieure
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Indiana University – Purdue University Indianapolis Department of Medical and Molecular Genetics pays non établi dans la noticeUniversité ou école supérieure
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Cincinnati Children's Hospital Medical Center pays non établi dans la noticeÉtablissement de santé
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University of Cincinnati Cincinnati Children’s Hospital Medical Center pays non établi dans la noticeUniversité ou école supérieure
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The Ohio State University Division of Cardiology pays non établi dans la noticeUniversité ou école supérieure
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The University of Texas Southwestern Medical Center Department of Molecular Genetics pays non établi dans la noticeÉtablissement de santé
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Centre National de la Recherche Scientifique pays non établi dans la noticeOrganisme public
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Université Côte d'Azur pays non établi dans la noticeUniversité ou école supérieure
and Blood Vascular Medicine Institute — University of Pittsburgh, University of Pittsburgh Medical Center et University of California System, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.