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

Integrative multiomics can elucidate pulmonary arterial hypertension (PAH) pathobiology but procuring human PAH lung samples is rare. Here, we leverage 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 identify two 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. Specifically, we find that asporin is upregulated in lungs and plasma of multiple independent PAH cohorts and correlates with reduced PAH severity. We show asporin inhibits proliferation and TGF-β/pSMAD2/3 signaling in pulmonary artery smooth muscle cells from PAH lungs. Finally, we demonstrate in Sugen-hypoxia rats that ASPN knockdown exacerbated PAH while 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.