Inflammation and oxidative stress accelerate atherosclerosis by promoting oxidation and arterial retention of apoB-containing lipoproteins.

The initiation and progression of atherosclerosis are driven by a complex, self-reinforcing network of vascular inflammation, oxidative stress, and lipoprotein entrapment within the arterial wall.

Mechanistic pathways of lipoprotein modification

• Enzymatic oxidation: Activated macrophages and neutrophils in the vascular wall release myeloperoxidase (MPO) and lipoxygenases (specifically 12/15-LOX). MPO generates highly reactive oxidants that cause protein cross-linking, nitration of tyrosine residues, and lysine modification on the apoB-100 protein. Concurrently, 12/15-LOX generates lipid hydroperoxides on the lipoprotein particle.
• Structural alterations: Early-stage, minimal oxidative modifications alter the surface charge and conformation of apolipoprotein B-100. This conformational change increases its binding affinity to negatively charged glycosaminoglycans on arterial proteoglycans, such as biglycan and versican.

Pathophysiological consequences and retention

• The response-to-retention cascade: Subendothelial entrapment of these modified apoB-containing lipoproteins within the extracellular matrix is the initiating event of atherogenesis. Once retained, their prolonged residence time increases their exposure to local oxidants, accelerating further oxidative modification.
• Vicious inflammatory feedback: Retained and oxidized lipoproteins act as pro-inflammatory stimuli. They drive the recruitment of leukocytes and the activation of macrophages into lipid-laden foam cells. These activated immune cells release more inflammatory mediators and oxidants, establishing a self-amplifying loop that accelerates plaque progression.

Bottom line

• Bottom line: Inflammation and oxidative stress promote the chemical modification of apoB-containing lipoproteins, enhancing their retention by arterial proteoglycans. This entrapment triggers a pathological feedback loop of localized vascular inflammation and progressive oxidation, accelerating the development of atherosclerosis.