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

• Published in: Circulation (New York, N.Y.) Vol. 150; no. 16; pp. 1268 - 1287
• Main Authors: Hong, Jason, Medzikovic, Lejla, Sun, Wasila, Wong, Brenda, Ruffenach, Grégoire, Rhodes, Christopher J, Brownstein, Adam, Liang, Lloyd L, Aryan, Laila, Li, Min, Vadgama, Arjun, Kurt, Zeyneb, Schwantes-An, Tae-Hwi, Mickler, Elizabeth A, Gräf, Stefan, Eyries, Mélanie, Lutz, Katie A, Pauciulo, Michael W, Trembath, Richard C, Perros, Frédéric, Montani, David, Morrell, Nicholas W, Soubrier, Florent, Wilkins, Martin R, Nichols, William C, Aldred, Micheala A, Desai, Ankit A, Trégouët, David-Alexandre, Umar, Soban, Saggar, Rajan, Channick, Richard, Tuder, Rubin M, Geraci, Mark W, Stearman, Robert S, Yang, Xia, Eghbali, Mansoureh
• Format: Journal Article
• Language: English
• Published: United States American Heart Association 15-10-2024
• Subjects: Animals; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; Female; Gene Expression Profiling; Gene Regulatory Networks; Genome-Wide Association Study; Humans; Life Sciences; Lung - metabolism; Lung - pathology; Male; Middle Aged; Multiomics; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; Pulmonary Arterial Hypertension - genetics; Pulmonary Arterial Hypertension - metabolism; Pulmonary Artery - drug effects; Pulmonary Artery - metabolism; Pulmonary Artery - pathology; Rats; Rats, Sprague-Dawley; Santé publique et épidémiologie; Signal Transduction; Smad2 Protein - genetics; Smad2 Protein - metabolism; Smad3 Protein - genetics; Smad3 Protein - metabolism; Transcriptome; gene expression profiling; pulmonary arterial hypertension; multiomics; Multiomics; Gene Expression Profiling; Pulmonary Arterial Hypertension
• ISSN: 0009-7322; 1524-4539; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.124.069864

Integrative multiomics can elucidate pulmonary arterial hypertension (PAH) pathobiology, but procuring human PAH lung samples is rare.
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.
We identified 2 potentially protective gene network modules associated with vascular cells, and we validated
, 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
knockdown exacerbated PAH and recombinant asporin attenuated PAH.
Our integrative systems biology approach to dissect the PAH lung transcriptome uncovered asporin as a novel protective target with therapeutic potential in PAH.