Atherogenesis: Apolipoprotein B and Plaque Progression

Atherosclerosis, the leading cause of heart attacks and strokes, develops when apolipoprotein B (ApoB)-containing lipoproteins infiltrate artery walls. These particles drive plaque buildup, narrowing blood vessels and increasing the risk of rupture. Understanding their role is essential for preventing cardiovascular disease.

Atherogenesis involves lipid accumulation, oxidative stress, inflammation, and calcification. Each factor influences plaque stability and the likelihood of life-threatening events.

Apolipoprotein B-Containing Lipoprotein Subtypes

Lipoproteins containing ApoB transport cholesterol and triglycerides through the bloodstream, contributing to plaque formation. Low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), and intermediate-density lipoprotein (IDL) each play distinct roles in this process.

LDL

LDL, the primary cholesterol carrier, is strongly linked to atherosclerosis. Each LDL particle contains a single ApoB-100 molecule, which facilitates its retention in the arterial wall. Once trapped, LDL undergoes oxidation, making it more atherogenic. Clinical studies consistently associate high LDL cholesterol (LDL-C) levels with increased cardiovascular risk. The 2019 European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) guidelines recommend reducing LDL-C below 55 mg/dL for high-risk individuals. Statins, PCSK9 inhibitors, and ezetimibe effectively lower LDL-C, with trials like FOURIER (2017) showing that aggressive reduction decreases major cardiovascular events.

VLDL

VLDL, produced by the liver, primarily transports triglycerides. Though less directly atherogenic than LDL, VLDL contributes to plaque formation as it is metabolized into smaller, denser remnants and LDL particles. Elevated VLDL is common in metabolic syndrome and type 2 diabetes, both associated with increased atherosclerosis risk. Lipoprotein lipase (LPL) hydrolyzes VLDL’s triglycerides, generating small, dense LDL, which penetrates arteries more easily. Therapies targeting VLDL include fibrates, omega-3 fatty acids, and niacin. The REDUCE-IT trial (2018) demonstrated that high-dose icosapent ethyl significantly lowers cardiovascular event rates by reducing triglyceride-rich lipoproteins.

IDL

IDL, an intermediate product of VLDL metabolism, retains atherogenic potential due to its cholesterol-rich composition. Elevated IDL is common in familial dyslipidemias, particularly type III hyperlipoproteinemia, a disorder caused by defective ApoE-mediated clearance. Unlike VLDL, IDL clearance depends on hepatic LDL receptors, influenced by genetic variations in the LDL receptor gene (LDLR). The Framingham Heart Study highlights IDL cholesterol as a predictor of coronary artery disease. Statins and PCSK9 inhibitors enhance LDL receptor activity, indirectly reducing IDL levels and mitigating their role in atherogenesis.

Endothelial Dysfunction and Lipoprotein Penetration

The endothelium regulates vascular homeostasis, but dysfunction increases permeability to ApoB-containing lipoproteins. Hypertension, hyperglycemia, and dyslipidemia disrupt endothelial function, allowing LDL and its remnants to enter the subendothelial space, initiating plaque development.

Once inside, LDL interacts with arterial proteoglycans such as biglycan and perlecan, which prolong its retention and increase its likelihood of modification. Studies using radiolabeled LDL tracers confirm that individuals with high cholesterol exhibit greater arterial LDL deposition.

Endothelial junctions also influence lipoprotein penetration. Normally, adherens and tight junction proteins maintain barrier integrity, but oxidized lipids and inflammatory cytokines weaken these connections, creating gaps for LDL transport. This dysfunction is particularly pronounced at arterial bifurcations, where disturbed blood flow weakens endothelial stability. Imaging techniques like intravital microscopy reveal increased lipoprotein infiltration in these regions, underscoring their vulnerability to early atherogenic changes.

Oxidative Modification and Foam Cell Formation

Once trapped in the arterial intima, LDL undergoes oxidative modification, enhancing its atherogenicity. Reactive oxygen species (ROS) drive this process, altering ApoB-100 and increasing LDL’s affinity for scavenger receptors. Unlike native LDL, oxidized LDL (oxLDL) accumulates unchecked, intensifying lipid deposition.

OxLDL perpetuates oxidative stress by stimulating further ROS production, leading to lipid peroxidation. Byproducts such as malondialdehyde and 4-hydroxynonenal modify LDL, making it more resistant to enzymatic degradation. Electron paramagnetic resonance spectroscopy reveals a strong correlation between oxLDL accumulation and plaque burden.

OxLDL promotes lipid aggregation, disrupting vascular homeostasis. It also contributes to cholesterol crystal formation, which destabilizes cellular structures and stiffens the arterial wall. Additionally, oxLDL crosslinks with collagen and elastin, reducing arterial flexibility and increasing plaque rupture risk.

Inflammatory Responses in Atheroma Development

Modified lipoproteins trigger inflammatory responses that drive atherogenesis. Endothelial cells release chemotactic factors like monocyte chemoattractant protein-1 (MCP-1), recruiting monocytes to the intima. These monocytes differentiate into macrophages, engulf oxLDL, and form foam cells, perpetuating inflammation.

Foam cells release pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), promoting smooth muscle cell proliferation and fibrous cap formation. However, chronic inflammation weakens this protective cap by stimulating matrix metalloproteinases (MMPs), which degrade collagen and elastin. This degradation increases plaque vulnerability, raising the risk of rupture and thrombosis.

Influence of Calcification on Plaque Stability

As plaques progress, calcium deposits accumulate, influencing stability. Unlike lipid-rich, rupture-prone plaques, heavily calcified lesions tend to be more stable. Calcification begins when vascular smooth muscle cells (VSMCs) and macrophages release matrix vesicles containing calcium and phosphate, which nucleate into hydroxyapatite crystals.

The morphology of calcification determines plaque vulnerability. Small, spotty microcalcifications, especially within thin fibrous caps, increase mechanical stress and rupture risk. Computational modeling shows these deposits concentrate tensile forces at the plaque surface. In contrast, extensive calcification reinforces plaque structure, reducing rupture likelihood.

Imaging modalities like coronary computed tomography angiography (CCTA) and positron emission tomography (PET) help differentiate high-risk from stable calcifications. Research into therapies targeting vascular calcification continues, with potential approaches focusing on phosphate metabolism and osteogenic signaling in VSMCs.

Genetic Variations Affecting Atherogenesis

Genetic differences influence atherosclerosis risk by altering lipid metabolism, endothelial function, and inflammation. Variants in LDLR, APOB, and PCSK9 affect LDL clearance, leading to elevated cholesterol and plaque formation. Familial hypercholesterolemia (FH), caused by mutations in these genes, results in lifelong high LDL-C, accelerating cardiovascular disease.

Beyond lipid metabolism, single nucleotide polymorphisms (SNPs) in inflammatory and endothelial genes also shape risk. Variants in IL6 and TNFA increase pro-inflammatory cytokine production, exacerbating arterial inflammation. Mutations in NOS3, which encodes endothelial nitric oxide synthase (eNOS), impair nitric oxide bioavailability, compromising vascular relaxation and increasing lipoprotein permeability.

Genome-wide association studies (GWAS) have identified numerous loci linked to atherosclerosis, highlighting its polygenic nature. While lifestyle and pharmacological interventions remain primary treatment strategies, advances in precision medicine may enable targeted therapies based on genetic profiles. Emerging gene-editing technologies, such as CRISPR-based approaches to modify PCSK9 expression, offer potential for long-term lipid regulation and atheroprotection.