How Inflammation Promotes Atherosclerosis: The Key Steps

▎Content Team of WuXi AppTec Edited

Lipid accumulation and hypertension are considered major risk factors for atherosclerotic cardiovascular disease (ASCVD). Cholesterol-lowering and antihypertensive medications are expected to effectively prevent and eliminate ASCVD. However, intervention strategies based on hypercholesterolemia and hypertension have failed to produce ideal results due to the exclusion of chronic vascular inflammation.

The residual inflammatory risk is considered a key coordinating factor affecting ASCVD. Inflammation drives the initiation of atherosclerosis, with lipoprotein entry, retention, and oxidative modification leading to endothelial injury, triggering both innate and adaptive immune responses. Recruited immune cells coordinate early atherosclerotic lesions by releasing pro-inflammatory cytokines, accelerating foam cell formation, causing intraplaque hemorrhage, secreting matrix-degrading enzymes, and promoting lesion progression, ultimately facilitating coronary syndrome through various inflammatory cascades.

Formation of Atherosclerotic Plaques

Atherosclerosis develops from the gradual involvement of multiple cells and their secretory products, leading to the transformation of fatty streaks into fibrofatty plaques, resulting in plaque rupture and thrombus formation.The development of atherosclerotic plaques is divided into six stages: pre-lesion (stages I, II, and III) and plaque formation (stages IV, V, and VI).

Due to increased levels of C-reactive protein (CRP), low-density lipoprotein (LDL), and tumor necrosis factor (TNF)-α, endothelial cell (EC) activity changes in stage I. This modification leads to the capture of LDL in the intima, which is prone to oxidation and glycation modifications. This mechanism converts LDL into modified lipoproteins, resulting in EC dysfunction, as evidenced by the appearance of chemokines (CD) and novel cell adhesion molecules. This process is accompanied by an inflammatory cascade (stage III), allowing plasma monocytes to penetrate the arterial intima along with platelets, T lymphocytes, and dendritic cells. Monocytes absorb modified lipoproteins and transform them into macrophage-derived foam cells. Smooth muscle cells enter the intima, leading to the production of a fibrous cap in stage IV. The formation of cholesterol crystals, extracellular matrix, and a large calcified core marks the progression to stage V. In stage VI, excessive release of cytokines weakens the fibrous cap, exhibiting complex plaques where EC damage and necrosis represent the final stage of atherosclerotic plaque formation.

Recruitment of Leukocytes and Formation of Foam Cells

Typically, the endothelium maintains a balance between vasodilation, vasoconstriction, pro-coagulation, and anti-coagulation events. However, endothelial cells can respond to damaging stimuli by upregulating nuclear factor κB (NF-κB), increasing the expression of leukocyte vascular cell adhesion molecules-1 (VCAM-1), intercellular adhesion molecule1 (ICAM-1), endothelin (ET-1), angiotensin (Ang) II, and pro-coagulation factors.

Upregulated receptor expression enhances the leakage of neutrophils and monocytes from the periphery to the subcutaneous space. Selectin-dependent adhesion molecules, including E-selectin and P-selectin, can induce low-affinity interactions between leukocytes and endothelial cells. This transient interaction leads to leukocyte activation, with very late antigen-4 (VLA-4) and its complementary ligand firmly adhering to activated endothelial cells VCAM-1 and ICAM-1. Macrophage colony-stimulating factor (M-CSF) exacerbates the situation by increasing macrophage numbers, enhancing oxidized low-density lipoprotein (ox-LDL) uptake, and foam cell formation.

Plaque accumulation is typically observed as yellow “fatty streaks,” representing the accumulation of foam cells in the vessel wall. Scavenger receptors (SR) CD36 and SR-A1 are primarily responsible for the uptake of ox-LDL by monocyte-derived macrophages. The ox-LDL and SR complex promotes the internalization of modified lipoproteins into cytoplasmic lipid droplets. The formation of macrophages and foam cells was initially thought to be beneficial due to their ox-LDL chelating potential. However, over time, foam cells lose the ability to digest lipoproteins. Increased reactive oxygen species (ROS) generated from endoplasmic reticulum stress trigger a cascade of apoptosis.

Next, foam cells activate CD36 and TLRs, which promote the production of cytokines and chemokines, amplifying local inflammatory responses by recruiting more circulating immune components to the lesions. Here, inflammation detects harmful stimuli and cleaves pro-IL-1β and IL-18 to their active forms. Meanwhile, the activation of scavenger receptors promotes the secretion of IL-1α, which plays a more significant role than IL-1β in atherosclerosis formation. The interaction of IL-1α, IL-1β, and IL-18 with their respective receptors leads to T cell activation and increased production of ROS and matrix metalloproteinases (MMPs). Immune cell infiltration promotes the release of pro-inflammatory cytokines and exacerbates atherosclerosis. On the other hand, foam cell hyperplasia is a process of clearing dead cell components from the body, which is disrupted, leading to the accumulation of debris and lipids in the cellular chamber, paving the way for the formation of a necrotic core rich in lipids with thrombotic characteristics.

Entry, Retention, and Modification of Lipoproteins: Early Mechanisms of Atherosclerotic Disease

The entry, retention, and modification of lipoproteins are related to the inflammatory response triggered by the accumulation of LDL in the arterial intima. Changes in endothelial membrane permeability, paracrine transport of LDL mediated by leaky cells and scavenger receptor B1 (SR-BI) and activin receptor-like kinase-1 (ALK-1) are linked to the accumulation of low-density lipoproteins. The destruction of the endothelial barrier forces the vessel to absorb more circulating LDL containing apolipoprotein B into the intima. Subsequently, LDL accumulates and is retained by binding to proteoglycans in the extracellular matrix through the intima. In addition, LDL undergoes oxidative modification through interactions with ROS and pro-oxidative enzymes produced by endothelial cells, smooth muscle cells, and macrophages.

This oxidative stress leads to cellular damage and disruption of normal functions in endothelial cells and macrophages. A review published by Nguyen et al. shows that ox-LDL can inhibit the production of nitric oxide (NO), thereby regulating the adhesion characteristics of resting platelets and leukocytes, vascular tone, fibrin integrity, and thrombus formation resistance. Furthermore, NO plays a balancing role in the abnormal proliferation of vascular smooth muscle cells (VSMCs). In the absence of NO, the expression of monocyte chemotactic protein-1 (MCP-1)/CCR2 and VCAM-1 is upregulated, enhancing the binding of monocytes and lymphocytes to the endothelium. Ox-LDL damage to vascular tissue indirectly promotes angiogenesis and formation of plaques, paving the way for the recruitment and proliferation of leukocytes in the arterial vessel wall.

Progression of Plaques

This migration leads to the proliferation of smooth muscle cells and the secretion of extracellular matrix macromolecules within the intima. Additionally, IL-1β and IL-6, TNF-α, and platelet-derived growth factor (PDGF) released by foam cells increase the migration and proliferation of smooth muscle cells and leukocytes, further exacerbating atherosclerosis and vascular inflammation. PDGF and heparinase released by foam cells promote coagulation and microthrombosis within the lesions. The metabolism of the extracellular matrix weakens the pre-formed fibrous cap and promotes the transition of fatty streaks to plaque formation stages. The metabolism is provided by the synthesis and degradation of extracellular matrix mediated by MMPs from smooth muscle cells. In the presence of interferon (IFN)-γ, collagen synthesis is inhibited, while PDGF and transforming growth factor β (TGF-β) stimulate the production of collagen in the stroma. Additionally, TGF-β enhances the formation of fibronectin and proteoglycans, triggering the expression of protease inhibitors and suppressing the release of proteolytic enzymes. Inflammatory cytokines stimulate foam cells to secrete MMPs, degrading collagen and elastin in the foam cap. Malnutrition and unhealthy lifestyles can also propagate necrosis deep in the thickened intima.

Plaque Rupture and Integrity

The key factors for plaque rupture are the extent of perfusion area, size of the lipid core, thickness of the fibrous cap, apoptosis of smooth muscle cells, and the disruption of the balance between proteolytic enzymes and plaque calcification. The integrity of the plaque is largely influenced by the metabolism of the extracellular matrix, which accelerates the breakdown of smooth muscle and foam cells through the activation of apoptotic pathways. Cell death, followed by the release of cellular contents, allows more lipids and debris to be absorbed, contributing to the enlargement of the lipid core size. Furthermore, the apoptosis of vascular smooth muscle (VSM) and accelerated degradation of the extracellular matrix further weakens the fibrous cap, increasing susceptibility to plaque rupture. Plaques lacking smooth muscle cells are more prone to rupture compared to thicker plaques, potentially triggering thrombus formation. Vessels are often prone to rupture, thus increasing the chances of intraplaque hemorrhage. Additionally, intraplaque hemorrhage enhances the destruction of the fibrous cap and vascular occlusion through intramural hematoma.

Calcification of plaques shifts tension to the interface between the fibrous cap and the vascular lumen, leading to plaque rupture. Once a plaque ruptures, thrombus-forming factors in the necrotic core are directly exposed to peripheral monocytes. Activated platelets initiate thrombus formation through platelet aggregation. On the other hand, thrombus formation and the atherosclerotic plaque environment disrupt the balance between coagulation and dissolution, ultimately increasing the likelihood of occlusive thrombosis.

Summary

Coronary perfusion insufficiency promotes the recruitment and activation of monocytes and T lymphocytes. These immune cells release pro-inflammatory IL-1, IL-6, TNF-α, and hs-CRP, contributing to atherosclerotic lesions, foam cell formation, endothelial dysfunction, enhanced vascular permeability, and recruitment of smooth muscle cells. The depletion of smooth muscle cells promotes plaque growth and cap development in coronary plaques. Unstable plaques are characterized by a thin fibrous cap and a lipid-rich necrotic core, particularly prone to rupture, thereby triggering acute thrombotic events. Therefore, these effector molecules are actively used in clinical settings as biomarkers to predict cardiovascular risk and therapeutic response in patients with coronary heart disease. Understanding the interplay between inflammatory propagation, atherosclerosis formation, and coronary heart disease is essential for recalibrating risk factors and elucidating new therapeutic intervention targets. Recognizing the heterogeneity of inflammatory processes and responses among individuals may aid in developing treatment strategies tailored to individual patients.

This article is authored by Zheng Gang from the International Cardiovascular Hospital of TEDA

How Inflammation Promotes Atherosclerosis: The Key Steps

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