. 2024 Oct 15;150(16):1268-1287.

doi: 10.1161/CIRCULATIONAHA.124.069864. Epub 2024 Aug 21.

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

Jason Hong^#¹, Lejla Medzikovic^#², Wasila Sun^#², Brenda Wong^#¹, Grégoire Ruffenach², Christopher J Rhodes³, Adam Brownstein¹, Lloyd L Liang¹, Laila Aryan², Min Li², Arjun Vadgama¹, Zeyneb Kurt⁴, Tae-Hwi Schwantes-An⁵, Elizabeth A Mickler⁵, Stefan Gräf⁶, Mélanie Eyries⁷, Katie A Lutz⁸, Michael W Pauciulo⁸, Richard C Trembath⁹, Frédéric Perros¹⁰, David Montani^{11

12

13}, Nicholas W Morrell⁶, Florent Soubrier¹⁴, Martin R Wilkins³, William C Nichols⁸, Micheala A Aldred⁵, Ankit A Desai⁵, David-Alexandre Trégouët¹⁵, Soban Umar², Rajan Saggar¹, Richard Channick¹, Rubin M Tuder¹⁶, Mark W Geraci¹⁷, Robert S Stearman^#⁵, Xia Yang^#¹⁸, Mansoureh Eghbali^#²

Affiliations

¹ Division of Pulmonary and Critical Care Medicine (J.H., B.W., A.B., L.L.L., A.V., R.S., R.C.), University of California, Los Angeles.
² Departments of Anesthesiology & Perioperative Medicine (L.M., W.S., G.R., L.A., M.L., S.U., M. Eghbali), University of California, Los Angeles.
³ National Heart and Lung Institute, Imperial College London, UK (C.J.R., M.R.W.).
⁴ Northumbria University, Newcastle Upon Tyne, UK (Z.K.).
⁵ Department of Medicine, Indiana University, Indianapolis (T.-H.S.-A., E.A.M., M.A.A., A.A.D., R.S.S.).
⁶ Department of Medicine, Victor Phillip Dahdaleh Heart & Lung Research Institute, University of Cambridge, UK (S.G., N.W.M.).
⁷ Hôpital Pitié-Salpêtrière, AP-HP, Département de Génétique, Paris, France (M. Eyries).
⁸ Department of Pediatrics, Division of Human Genetics, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, OH (K.A.L., M.W.P., W.C.N.).
⁹ Department of Medical & Molecular Genetics, Faculty of Life Sciences & Medicine, King's College London, UK (R.C.T.).
¹⁰ CarMeN Laboratory, INSERM U1060, INRAE U1397, Université Claude Bernard Lyon 1, Pierre-Bénite, France (F.P.).
¹¹ AP-HP, Service de Pneumologie, Hôpital Bicêtre, Le Kremlin Bicêtre, France (D.M.).
¹² Université Paris-Saclay, Le Kremlin Bicêtre, France (D.M.).
¹³ UMR_S 999, Université Paris-Saclay, INSERM, Groupe Hospitalier Marie-Lannelongue-Saint Joseph, Le Plessis-Robinson, France (D.M.).
¹⁴ UMR_S 1166, Sorbonne Université, INSERM, Paris, France (F.S.).
¹⁵ Bordeaux Population Health Research Center, INSERM, Université Bordeaux, France (D.-A.T.).
¹⁶ Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Aurora (R.M.T.).
¹⁷ Department of Medicine, University of Pittsburgh, PA (M.W.G.).
¹⁸ Integrative Biology and Physiology (X.Y.), University of California, Los Angeles.

^# Contributed equally.

PMID: 39167456
PMCID: PMC11473243 (available on 2025-10-15)
DOI: 10.1161/CIRCULATIONAHA.124.069864

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

Jason Hong et al. Circulation. 2024.

. 2024 Oct 15;150(16):1268-1287.

doi: 10.1161/CIRCULATIONAHA.124.069864. Epub 2024 Aug 21.

Authors

Affiliations

¹ Division of Pulmonary and Critical Care Medicine (J.H., B.W., A.B., L.L.L., A.V., R.S., R.C.), University of California, Los Angeles.
² Departments of Anesthesiology & Perioperative Medicine (L.M., W.S., G.R., L.A., M.L., S.U., M. Eghbali), University of California, Los Angeles.
³ National Heart and Lung Institute, Imperial College London, UK (C.J.R., M.R.W.).
⁴ Northumbria University, Newcastle Upon Tyne, UK (Z.K.).
⁵ Department of Medicine, Indiana University, Indianapolis (T.-H.S.-A., E.A.M., M.A.A., A.A.D., R.S.S.).
⁶ Department of Medicine, Victor Phillip Dahdaleh Heart & Lung Research Institute, University of Cambridge, UK (S.G., N.W.M.).
⁷ Hôpital Pitié-Salpêtrière, AP-HP, Département de Génétique, Paris, France (M. Eyries).
⁸ Department of Pediatrics, Division of Human Genetics, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, OH (K.A.L., M.W.P., W.C.N.).
⁹ Department of Medical & Molecular Genetics, Faculty of Life Sciences & Medicine, King's College London, UK (R.C.T.).
¹⁰ CarMeN Laboratory, INSERM U1060, INRAE U1397, Université Claude Bernard Lyon 1, Pierre-Bénite, France (F.P.).
¹¹ AP-HP, Service de Pneumologie, Hôpital Bicêtre, Le Kremlin Bicêtre, France (D.M.).
¹² Université Paris-Saclay, Le Kremlin Bicêtre, France (D.M.).
¹³ UMR_S 999, Université Paris-Saclay, INSERM, Groupe Hospitalier Marie-Lannelongue-Saint Joseph, Le Plessis-Robinson, France (D.M.).
¹⁴ UMR_S 1166, Sorbonne Université, INSERM, Paris, France (F.S.).
¹⁵ Bordeaux Population Health Research Center, INSERM, Université Bordeaux, France (D.-A.T.).
¹⁶ Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Aurora (R.M.T.).
¹⁷ Department of Medicine, University of Pittsburgh, PA (M.W.G.).
¹⁸ Integrative Biology and Physiology (X.Y.), University of California, Los Angeles.

^# Contributed equally.

PMID: 39167456
PMCID: PMC11473243 (available on 2025-10-15)
DOI: 10.1161/CIRCULATIONAHA.124.069864

Erratum in

Correction to: Integrative Multiomics in the Lung Reveals a Protective Role of Asporin in Pulmonary Arterial Hypertension.
Hong J, Medzikovic L, Sun W, Wong B, Ruffenach G, Rhodes CJ, Brownstein A, Liang LL, Aryan L, Li M, Vadgama A, Kurt Z, Schwantes-An TH, Mickler EA, Gräf S, Eyries M, Lutz KA, Pauciulo MW, Trembath RC, Perros F, Montani D, Morrell NW, Soubrier F, Wilkins MR, Nichols WC, Aldred MA, Desai AA, Trégouët DA, Umar S, Saggar R, Channick R, Tuder RM, Geraci MW, Stearman RS, Yang X, Eghbali M. Hong J, et al. Circulation. 2025 Apr 8;151(14):e921. doi: 10.1161/CIR.0000000000001331. Epub 2025 Apr 7. Circulation. 2025. PMID: 40193543 No abstract available.

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.

Keywords: gene expression profiling; multiomics; pulmonary arterial hypertension.

PubMed Disclaimer

Conflict of interest statement

Drs Hong, Medzikovic, and Eghbali are coinventors of US provisional patent application 63/544,027, “Asporin in Pulmonary Hypertension.”

References

1. Stearman RS, Bui QM, Speyer G, Handen A, Cornelius AR, Graham BB, Kim S, Mickler EA, Tuder RM, Chan SY, Geraci MW. Systems Analysis of the Human Pulmonary Arterial Hypertension Lung Transcriptome. Am J Respir Cell Mol Biol. 2019. Jun;60(6):637–649. - PMC - PubMed
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Integrative Multiomics in the Lung Reveals a Protective Role of Asporin in Pulmonary Arterial Hypertension

Affiliations

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

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources