TY - JOUR
T1 - Integrative Multiomics in the Lung Reveals a Protective Role of Asporin in Pulmonary Arterial Hypertension
AU - Hong, Jason
AU - Medzikovic, Lejla
AU - Sun, Wasila
AU - Wong, Brenda
AU - Ruffenach, Grégoire
AU - Rhodes, Christopher J.
AU - Brownstein, Adam
AU - Liang, Lloyd L.
AU - Aryan, Laila
AU - Li, Min
AU - Vadgama, Arjun
AU - Kurt, Zeyneb
AU - Schwantes-An, Tae-Hwi
AU - Mickler, Elizabeth A.
AU - Gräf, Stefan
AU - Eyries, Mélanie
AU - Lutz, Katie A.
AU - Pauciulo, Michael W.
AU - Trembath, Richard C.
AU - Perros, Frédéric
AU - Montani, David
AU - Morrell, Nicholas W.
AU - Soubrier, Florent
AU - Wilkins, Martin R.
AU - Nichols, William C.
AU - Aldred, Micheala A.
AU - Desai, Ankit A.
AU - Trégouët, David-Alexandre
AU - Umar, Soban
AU - Saggar, Rajan
AU - Channick, Richard
AU - Tuder, Rubin M.
AU - Geraci, Mark W.
AU - Stearman, Robert S.
AU - Yang, Xia
AU - Eghbali, Mansoureh
PY - 2024/8/21
Y1 - 2024/8/21
N2 - 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.
AB - 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.
KW - gene expression profiling
KW - multiomics
KW - pulmonary arterial hypertension
U2 - 10.1161/circulationaha.124.069864
DO - 10.1161/circulationaha.124.069864
M3 - Article
SN - 0009-7322
JO - Circulation
JF - Circulation
ER -
