Abstract 10096: Genetic Control of Lysosomal Dysfunction Reprograms Sterol Metabolism in Pulmonary Arterial Hypertension

Abstract

Background : Vascular inflammation critically regulates endothelial pathophenotypes, yet causative mechanisms remain incompletely defined, particularly in pulmonary arterial hypertension (PAH). Immune dysregulation and metabolic reprogramming are recognized tenets of PAH pathogenesis, but a unifying theory connecting the two has not been established. Methods & Results: Guided by an unbiased, metabolome-wide association study from the multicenter PAH Biobank cohort (N=2,666) that identified a proinflammatory sterol and bile acid metabolite plasma signature significantly associated with PAH mortality (adjusted P values<1.1x10 -6 ), we found in pulmonary arterial endothelial cells (ECs) that induction of the nuclear receptor coactivator 7 (NCOA7) tempered the generation of proinflammatory sterols by bolstering lysosomal acidification and constraining EC immunoactivation. Conversely, reduced NCOA7 promoted lysosomal dysfunction, resulting in sterol- and bile acid-driven inflammation and EC phenotypes consistent with PAH. Notably, the common variant intronic SNP rs11154337 in NCOA7 was found to control NCOA7 levels, lysosome activity, sterol and bile acid production, and EC immunoactivation in isogenic, CRISPR-Cas9, SNP-edited, iPSC-derived ECs, indicating a potentially widespread genetic predisposition to NCOA7 deficiency. Correspondingly, SNP rs11154337 was associated with PAH severity as noted by six-minute walk distance ( P =0.0130, β=58.15, 95% CI [14.45-119.36]) and mortality ( P =0.0250; hazard ratio=0.4368, 95% CI [0.21-0.90]) in an independent, single-center PAH cohort (N=93). In vivo , mice deficient for Ncoa7 or treated with exogenous 7α-hydroxy-3-oxo-4-cholestenoic acid (7HOCA)—chosen as a representative metabolite from the sterol signature associated with mortality in the PAH Biobank—demonstrated worsened hemodynamic and histological indices of PAH. Conclusions: Our work establishes a genetic and metabolic paradigm that links lysosomal biology and sterol and bile acid processes with EC inflammation. This paradigm carries broad implications not only on molecular diagnostic and therapeutic development in PAH but also in other vascular disorders dependent upon acquired and innate immune regulation.