How ApoB Lipoproteins Drive Plaque Formation and What We Can Do About It
A landmark 2025 review reveals the step-by-step molecular mechanisms by which apoB-containing lipoproteins initiate and grow atherosclerotic plaques.
Summary
This comprehensive 2025 review in Nature Reviews Cardiology examines how apolipoprotein B-containing lipoproteins — including LDL, triglyceride-rich lipoproteins, and lipoprotein(a) — drive atherosclerosis. LDL enters arterial walls via transcytosis and becomes trapped by proteoglycans, triggering inflammation, foam cell formation, and necrotic core development. While LDL is most abundant, other apoB-containing lipoproteins are far more atherogenic per particle. The authors highlight emerging therapeutic targets focused on lowering circulating lipoprotein levels and dampening maladaptive arterial wall responses, offering a roadmap for reducing cardiovascular disease burden.
Detailed Summary
Atherosclerosis remains the leading driver of cardiovascular mortality worldwide, and understanding precisely how plaques form is essential for developing better preventive and therapeutic strategies. This 2025 review in Nature Reviews Cardiology synthesizes current knowledge on the central role of apolipoprotein B (apoB)-containing lipoproteins in this process.
ApoB is the structural backbone of LDL, triglyceride-rich lipoproteins (TRLs), and lipoprotein(a). The authors detail how LDL — the most abundant cholesterol-rich lipoprotein in plasma — initiates atherosclerosis by crossing the endothelium via transcytosis. In susceptible arterial regions, LDL becomes retained in the subendothelial space through binding of apoB to proteoglycans, a critical early step in plaque formation.
Once retained, LDL undergoes modification that amplifies its pathological effects. Modified LDL promotes further retention, releases bioactive lipid mediators that activate inflammatory cascades in vascular cells, and stimulates adaptive immune responses. Macrophages engulf modified LDL to become foam cells, which eventually die due to overwhelmed lipid-handling capacity. The accumulation of dead cells and cholesterol crystals forms the necrotic core — a hallmark of vulnerable atherosclerotic plaques.
The review also highlights that while TRLs and lipoprotein(a) are less abundant than LDL, they carry substantially greater atherogenicity per particle. They likely share LDL's mechanistic pathways but may also engage additional disease-promoting mechanisms not yet fully characterized.
For intervention, the authors identify reducing plasma lipoprotein levels and modulating arterial wall inflammatory responses as the most promising therapeutic axes. This aligns with growing clinical interest in aggressive lipid-lowering therapies (statins, PCSK9 inhibitors, inclisiran) and emerging anti-inflammatory approaches. A key caveat is that this is a review based on existing evidence, so no new experimental data are presented.
Key Findings
- LDL initiates atherosclerosis by crossing the endothelium and binding arterial proteoglycans via apoB, triggering plaque formation.
- Modified LDL drives inflammation, foam cell formation, and necrotic core development through lipid release and immune activation.
- TRLs and lipoprotein(a) are far more atherogenic per particle than LDL, possibly through additional pathogenic mechanisms.
- Lowering plasma apoB-containing lipoproteins and dampening arterial wall maladaptive responses are key therapeutic targets.
- Cholesterol crystallization and dead cell accumulation are identified as defining features of advanced plaque necrotic cores.
Methodology
This is a narrative expert review published in Nature Reviews Cardiology, synthesizing existing mechanistic and clinical research on apoB-containing lipoproteins. No original experimental data are presented. The authors draw on molecular biology, epidemiology, and clinical trial evidence to construct a comprehensive mechanistic framework.
Study Limitations
As a review article, this work does not present new experimental data and is subject to the limitations of the underlying studies synthesized. Mechanisms specific to TRLs and lipoprotein(a) beyond LDL pathways are noted but remain incompletely characterized. The review may not fully capture emerging research published after its submission date.
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