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

TL;DR

High levels of Asporin in atherosclerotic plaques make them more stable and reduce the risk of cardiovascular events.

Contribution

ASPN is newly identified as a regulator of vascular calcification and plaque stability in atherosclerosis.

Findings

ASPN levels are higher in asymptomatic plaques and correlate with plaque stability markers.

ASPN overexpression in smooth muscle cells reduces matrix mineralization in vitro.

High ASPN is associated with fewer future cardiovascular events in patients.

Abstract

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.

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.

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.

Graphical AbstractHigh ASPN levels in atherosclerotic plaques are associated with reduced vascular calcification and a more stable plaque phenotype, while low ASPN levels predict future cardiovascular events. Created in BioRender. Gialeli, C. (2025). https://BioRender.com/j15d480For image description, please refer to the figure legend and surrounding text.

High ASPN levels in atherosclerotic plaques are associated with reduced vascular calcification and a more stable plaque phenotype, while low ASPN levels predict future cardiovascular events. Created in BioRender. Gialeli, C. (2025). https://BioRender.com/j15d480

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