Elevated Asporin expression in human atherosclerotic plaques promotes their stability and reduces the risk for cardiovascular events

Cardiovascular Research, vol. 122, pp. 349–362

Abstract

AIMS: Vascular atherosclerotic calcification is a pathological process marked by the abnormal deposition of calcium minerals in the intima. Asporin (ASPN) is a small leucine-rich proteoglycan which interacts with collagen and calcium. Due to its role in matrix mineralization, we hypothesized that ASPN might act as a regulator of vascular calcification, thereby promoting atherosclerotic plaque stability. METHODS AND RESULTS: ASPN protein, analysed by ELISA, was quantified in 176 carotid endarterectomy plaques (Carotid Plaque Imaging Project cohort, including 98 patients with cerebrovascular symptoms and 78 asymptomatic patients). Plaque composition was assessed by histological, biochemical, and immunological assays, along with bulk RNA sequencing, to investigate the role of ASPN in atherosclerosis. Patients donating plaques were followed up for post-operative cardiovascular events, median follow-up 6.58 years. The effect of ASPN on smooth muscle cell (SMC) differentiation and matrix mineralization was investigated in vitro using human vascular SMCs overexpressing ASPN. Increased ASPN protein levels were observed in plaques from asymptomatic patients compared with patients with cerebrovascular symptoms. ASPN protein levels were positively associated with markers of plaque stability and regulation of extracellular matrix remodelling while showing an inverse relationship with calcification. Patients with high intraplaque ASPN had a lower risk for future cardiovascular events. Mechanistically, ASPN overexpression in vascular SMCs reduced matrix mineralization in vitro, supporting its potential role in plaque stabilization. CONCLUSION: ASPN is a regulator of vascular calcification in atherosclerosis, promoting a plaque phenotype that is less prone to rupture. Additionally, high ASPN levels are associated with fewer future cardiovascular events.

Authors 13

1. Chrysostomi Gialeli

   Lund University

   Affiliation as printed

   Cardiovascular Research Translational Studies, Department of Clinical Sciences Malmö, Lund University , Malmö ,

2. Nicoline W. Thorsen

   University of Copenhagen · Lund University

   Affiliation as printed

   Cardiovascular Research Translational Studies, Department of Clinical Sciences Malmö, Lund University , Malmö ,

   Department of Biomedical Sciences, University of Copenhagen , Copenhagen ,

3. Dianne Acoba

   Lund University

   Affiliation as printed

   Cardiovascular Research Translational Studies, Department of Clinical Sciences Malmö, Lund University , Malmö ,

4. Jiangming Sun

   Lund University

   Affiliation as printed

   Cardiovascular Research Translational Studies, Department of Clinical Sciences Malmö, Lund University , Malmö ,

5. Luke F. Gamon

   University of Copenhagen · Lund University

   Affiliation as printed

   Cardiovascular Research Translational Studies, Department of Clinical Sciences Malmö, Lund University , Malmö ,

   Department of Biomedical Sciences, University of Copenhagen , Copenhagen ,

6. Annelie Shami

   Lund University

   Affiliation as printed

   Cardiovascular Research Translational Studies, Department of Clinical Sciences Malmö, Lund University , Malmö ,

7. Mihaela Nitulescu

   Lund University

   Affiliation as printed

   Cardiovascular Research Translational Studies, Department of Clinical Sciences Malmö, Lund University , Malmö ,

8. Ana Flor Persson

   Lund University

   Affiliation as printed

   Cardiovascular Research Translational Studies, Department of Clinical Sciences Malmö, Lund University , Malmö ,

9. Eva Bengtsson

   Lund University · Malmö University

   Affiliation as printed

   Biofilms–Research Center for Biointerfaces, Malmö University , Malmö ,

   Cardiovascular Research Translational Studies, Department of Clinical Sciences Malmö, Lund University , Malmö ,

   Department of Biomedical Science, Faculty of Health and Society, Malmö University , Malmö ,

10. Michael J. Davies

    University of Copenhagen

    Affiliation as printed

    Department of Biomedical Sciences, University of Copenhagen , Copenhagen ,

11. Andreas Edsfeldt

    Lund University · Skåne University Hospital

    Affiliation as printed

    Cardiovascular Research Translational Studies, Department of Clinical Sciences Malmö, Lund University , Malmö ,

    Department of Cardiology, Skåne University Hospital , Malmö ,

    Wallenberg Center for Molecular Medicine, Lund University , Malmö ,

12. Claudia Goettsch Aachen Department of Internal Medicine I Division of Cardiology, Medical Faculty

    RWTH Aachen University · Technische Universität Dresden

    Affiliation as printed

    Department of Internal Medicine I, Division of Cardiology, Medical Faculty, RWTH Aachen University ,

    Faculty of Medicine Carl Gustav Carus, Institute of Physiology, Technical University Dresden , Dresden ,

13. Isabel Gonçalves

    Lund University · Skåne University Hospital

    Affiliation as printed

    Cardiovascular Research Translational Studies, Department of Clinical Sciences Malmö, Lund University , Malmö ,

    Department of Cardiology, Skåne University Hospital , Malmö ,