APRIL limits atherosclerosis by binding to heparan sulfate proteoglycans

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.