Integrative Multiomics in the Lung Reveals a Protective Role of Asporin in Pulmonary Arterial Hypertension

Jason Hong, Lejla Medzikovic, Wasila Sun, Brenda Wong, Grégoire Ruffenach, Christopher J. Rhodes, Adam Brownstein, Lloyd L. Liang, Laila Aryan, Min Li, Arjun Vadgama, Zeyneb Kurt, Tae-Hwi Schwantes-An, Elizabeth A. Mickler, Stefan Gräf, Mélanie Eyries, Katie A. Lutz, Michael W. Pauciulo, Richard C. Trembath, Frédéric Perros, David Montani, Nicholas W. Morrell, Florent Soubrier, Martin R. Wilkins, William C. Nichols, Micheala A. Aldred, Ankit A. Desai, David-Alexandre Trégouët, Soban Umar, Rajan Saggar, Richard Channick, Rubin M. Tuder, Mark W. Geraci, Robert S. Stearman, Xia Yang, Mansoureh Eghbali
University of California, Los Angeles. Imperial College London. Northumbria University. Indiana University. University of Cambridge. Hôpital Pitié-Salpêtrière. Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine. King’s College. Université Claude Bernard Lyon 1. Hôpital Bicêtre. Université Paris-Saclay. Sorbonne Université. Université Bordeaux. University of Colorado. University of Pittsburgh.
United States, United Kingdom and France

Circulation
Circulation 2024;
DOI: 10.1161/CIRCULATIONAHA.124.069864

Abstract
Background: Integrative multiomics can elucidate pulmonary arterial hypertension (PAH) pathobiology, but procuring human PAH lung samples is rare.
Methods: We leveraged transcriptomic profiling and deep phenotyping of the largest multicenter PAH lung biobank to date (96 disease and 52 control) by integration with clinicopathologic data, genome-wide association studies, Bayesian regulatory networks, single-cell transcriptomics, and pharmacotranscriptomics.
Results: We identified 2 potentially protective gene network modules associated with vascular cells, and we validated ASPN, coding for asporin, as a key hub gene that is upregulated as a compensatory response to counteract PAH. We found that asporin is upregulated in lungs and plasma of multiple independent PAH cohorts and correlates with reduced PAH severity. We show that asporin inhibits proliferation and transforming growth factor-β/phosphorylated SMAD2/3 signaling in pulmonary artery smooth muscle cells from PAH lungs. We demonstrate in Sugen-hypoxia rats that ASPN knockdown exacerbated PAH and recombinant asporin attenuated PAH.
Conclusions: Our integrative systems biology approach to dissect the PAH lung transcriptome uncovered asporin as a novel protective target with therapeutic potential in PAH.

Category
Pulmonary Vascular Pathology
Genetic Factors Associated with Pulmonary Vascular Disease
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Animal Models of Pulmonary Vascular Disease and Therapy

Age Focus: No Age-Related Focus

Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication

Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes

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