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Updated: Oct 22, 2025
A Human Ex Vivo Atherosclerotic Plaque Model to Study Lesion Biology
Published on: May 6, 2014
APRIL limits atherosclerosis by binding to heparan sulfate proteoglycans
Dimitrios Tsiantoulas1, Mahya Eslami2, Georg Obermayer3,4
1Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria. dimitris.tsiantoulas@meduniwien.ac.at.
Insights
A proliferation-inducing ligand (APRIL) protects against atherosclerosis by binding to heparan sulfate proteoglycans, reducing LDL retention and inflammation. This discovery offers new insights into cardiovascular disease prevention.
Area of Science:
- Cardiovascular Biology
- Immunology
- Proteoglycan Research
Background:
- Atherosclerotic cardiovascular disease is a leading global cause of mortality, driven by plaque formation.
- Low-density lipoproteins (LDL) trapping in arteries initiates plaque development, leading to inflammation.
- The role of A proliferation-inducing ligand (APRIL) in this process is not well understood.
Purpose of the Study:
- To investigate the role of APRIL in the development of atherosclerosis.
- To elucidate the mechanism by which APRIL influences atherosclerotic plaque formation.
- To explore the potential of APRIL as a therapeutic target for cardiovascular disease.
Main Methods:
- Genetic ablation and antibody-mediated depletion of APRIL in mouse models of atherosclerosis.
- Analysis of LDL retention, macrophage accumulation, and necrotic core formation in atherosclerotic plaques.
- Investigation of APRIL's interaction with heparan sulfate proteoglycans (HSPGs), specifically HSPG2.
- Assessment of serum non-canonical APRIL (nc-APRIL) levels and their association with cardiovascular mortality in patients.
Main Results:
- APRIL deficiency or depletion exacerbated atherosclerosis in mice.
- APRIL protects against atherosclerosis by binding to HSPG2, limiting LDL retention and macrophage accumulation.
- Mice with heparan sulfate-deficient HSPG2 showed no effect of APRIL depletion on atherosclerosis.
- Treatment with an anti-APRIL antibody reduced experimental atherosclerosis.
- Serum nc-APRIL levels were associated with long-term cardiovascular mortality in patients.
Conclusions:
- APRIL plays a protective role in atherosclerosis by modulating LDL retention and inflammation via HSPG2.
- Targeting APRIL, particularly the HSPG-binding form, may offer a novel therapeutic strategy for cardiovascular disease.
- Non-canonical APRIL (nc-APRIL) serves as a potential biomarker for cardiovascular risk.
Abstract:
Atherosclerotic cardiovascular disease causes heart attacks and strokes, which are the leading causes of mortality worldwide1. The formation of atherosclerotic plaques is initiated when low-density lipoproteins bind to heparan-sulfate proteoglycans (HSPGs)2 and become trapped in the subendothelial space of large and medium size arteries, which leads to chronic inflammation and remodelling of the artery wall2. A proliferation-inducing ligand (APRIL) is a cytokine that binds to HSPGs3, but the physiology of this interaction is largely unknown. Here we show that genetic ablation or antibody-mediated depletion of APRIL aggravates atherosclerosis in mice. Mechanistically, we demonstrate that APRIL confers atheroprotection by binding to heparan sulfate chains of heparan-sulfate proteoglycan 2 (HSPG2), which limits the retention of low-density lipoproteins, accumulation of macrophages and formation of necrotic cores. Indeed, antibody-mediated depletion of APRIL in mice expressing heparan sulfate-deficient HSPG2 had no effect on the development of atherosclerosis. Treatment with a specific anti-APRIL antibody that promotes the binding of APRIL to HSPGs reduced experimental atherosclerosis. Furthermore, the serum levels of a form of human APRIL protein that binds to HSPGs, which we termed non-canonical APRIL (nc-APRIL), are associated independently of traditional risk factors with long-term cardiovascular mortality in patients with atherosclerosis. Our data reveal properties of APRIL that have broad pathophysiological implications for vascular homeostasis.
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