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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE254617 | GEO | 2024/05/22

REPOSITORIES: GEO

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Project description:Objective: Pulmonary complications in systemic sclerosis (SSc), including pulmonary fibrosis (PF) and pulmonary arterial hypertension (PAH), are the leading cause of mortality. We compared the molecular fingerprint of SSc lung tissues and matching primary lung fibroblasts to those of normal donors, and patients with idiopathic pulmonary fibrosis (IPF) and idiopathic pulmonary arterial hypertension (IPAH). Methods: Lung tissues were obtained from 33 patients with SSc who underwent lung transplantation. Tissues and cells from a subgroup of SSc patients with predominantly PF or PAH were compared to those from normal donors, patients with IPF, or IPAH. Microarray data was analyzed using Efficiency Analysis for determination of optimal data processing methods. Real time PCR and immunohistochemistry were used to confirm differential levels of mRNA and protein, respectively. Results: We identified a consensus of 242 and 335 genes that were differentially expressed in lungs and primary fibroblasts, respectively. Enriched function groups in SSc-PF and IPF lungs included fibrosis, insulin-like growth factor signaling and caveolin-mediated endocytosis. Functional groups shared by SSc-PAH and IPAH lungs included antigen presentation, chemokine activity, and IL-17 signaling. Conclusion: Using microarray analysis on carefully phenotyped SSc and comparator lung tissues, we demonstrated distinct molecular profiles in tissues and fibroblasts of patients with SSc-associated lung disease compared to idiopathic forms of lung disease. Unique molecular signatures were generated that are disease- (SSc) and phenotype- (PF vs PAH) specific. These signatures provide new insights into pathogenesis and potential therapeutic targets for SSc lung disease. Lung tissues were obtained from 33 patients with SSc who underwent lung transplantation. Tissues and cells from a subgroup of SSc patients with predominantly PF or PAH were compared to those from normal donors, patients with IPF, or IPAH. Microarray data was analyzed using Efficiency Analysis for determination of optimal data processing methods. Real time PCR and immunohistochemistry were used to confirm differential levels of mRNA and protein, respectively.

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

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