Overview of Atherosclerosis and Its Role in Coronary Heart Disease

Atherosclerosis is a chronic inflammatory disease characterized by the buildup of plaques in arterial walls, primarily due to lipid accumulation, immune cell infiltration, and fibrous remodeling. In coronary heart disease (CHD), this process specifically affects the coronary arteries, leading to reduced blood flow, ischemia, angina, myocardial infarction, and increased cardiovascular mortality. At the molecular level, atherosclerosis involves interconnected pathways of endothelial dysfunction, oxidative stress, dysregulated lipid metabolism, chronic inflammation, and cellular phenotypic changes. These mechanisms initiate plaque formation, promote progression, and drive instability, culminating in thrombotic events in CHD. Recent research emphasizes the role of genetic factors like clonal hematopoiesis, epigenetic modifications (e.g., miRNAs), and metabolic shifts (e.g., hypoxia-induced signaling) in exacerbating these processes.

Initiation: Endothelial Dysfunction and Lipid Retention/Oxidation

Atherosclerosis begins with endothelial dysfunction, where the vascular endothelium loses its protective barrier function, becoming permeable to lipids and prothrombotic. Risk factors such as hyperlipidemia, hypertension, smoking, and hyperglycemia trigger this via shear stress and oxidative damage, reducing nitric oxide (NO) bioavailability through uncoupling of endothelial nitric oxide synthase (eNOS). This leads to reactive oxygen species (ROS) production by NADPH oxidases (e.g., NOX4) and mitochondrial dysfunction, promoting vasoconstriction and leukocyte adhesion. Key adhesion molecules upregulated include vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and selectins (E- and P-selectin), while chemokines like monocyte chemotactic protein-1 (MCP-1/CCL2) and CXCL12 facilitate immune cell tethering via receptors such as CCR2 and CXCR4.

Low-density lipoprotein (LDL) particles, particularly cholesterol-rich LDL-c, infiltrate the subendothelial intima due to this increased permeability. Retained LDL undergoes oxidation by ROS and reactive nitrogen species (RNS) from enzymes like xanthine oxidoreductase (XOR) and NADPH oxidases, forming oxidized LDL (oxLDL). OxLDL acts as a damage-associated molecular pattern (DAMP), activating Toll-like receptor 4 (TLR4) and promoting further endothelial inflammation via NF-κB signaling. Hyperuricemia exacerbates this by elevating uric acid (UA), which activates XOR to generate ROS, impairs autophagy via NRF2 dysfunction, and induces ferroptosis (iron-dependent lipid peroxidation). In CHD, endothelial dysfunction manifests as coronary microvascular dysfunction (CMD), impairing microcirculatory flow regulation and contributing to ~50% of anginal symptoms without obstructive epicardial disease.

Progression: Monocyte Recruitment and Foam Cell Formation

Circulating monocytes, stimulated by hypercholesterolemia and systemic inflammation, are recruited to the intima via chemokine gradients (e.g., CCL2-CCR2 axis) and adhesion molecules. Classical monocytes predominate, differentiating into macrophages upon infiltration. In advanced plaques, clonal hematopoiesis of indeterminate potential (CHIP) with mutations like TET2 enhances monocytosis by boosting IL-6 and IL-1β secretion, accelerating recruitment and plaque growth. Neutrophils contribute via neutrophil extracellular traps (NETs), which trap monocytes, amplify ROS, and promote endothelial damage.

Macrophages engulf oxLDL via scavenger receptors (e.g., CD36, SR-A), leading to foam cell formation—lipid-laden cells central to plaque expansion. This uptake triggers cholesterol esterification and metabolic rewiring toward aerobic glycolysis, mediated by hypoxia-inducible factor-1α (HIF-1α) and PKM2, upregulating glucose transporters like GLUT-1 (SLC2A1). Impaired cholesterol efflux via ATP-binding cassette transporters (ABCA1/ABCG1) exacerbates accumulation, regulated by miRNAs such as miR-33 (which suppresses efflux) and miR-320b (which enhances it). Epigenetic factors like USP9X deubiquitination prevent lipid overload, while exosomal miR-21-3p from nicotine-exposed macrophages promotes foam cell persistence via PTEN inhibition. In CHD, foam cells in coronary plaques drive chronic coronary syndrome by expanding lipid cores and releasing proinflammatory signals.

Inflammation: Central Driver of Atherogenesis

Inflammation orchestrates atherosclerosis progression through innate and adaptive immune responses. The NLRP3 inflammasome, activated by oxLDL, cholesterol crystals, and hypoxia, cleaves caspase-1 to release IL-1β and IL-18, recruiting more leukocytes and inducing pyroptosis via gasdermin D. NF-κB pathway amplification occurs via oxLDL-induced RIPK1, TRIM64-mediated IκBα ubiquitination, and vimentin/FAK signaling post-CD36 binding. Hypoxia in plaque cores stabilizes HIF-1α, promoting mTORC1 activation, NF-κB translocation, and cytokine storms (e.g., TNF-α, IL-6, IL-17). HMGB1 release under hypoxia binds RAGE to further activate NLRP3. Macrophages polarize toward proinflammatory M1 phenotypes (via IFN-γ/LPS), expressing high PLIN2/TREM1 for enhanced lipid uptake, while M2 (anti-inflammatory) traits wane due to PPAR-γ suppression.

T cells (e.g., Th17) and dendritic cells amplify this via IFN-γ and IL-17, while epicardial fat in CHD patients shows elevated M1 infiltration and cytokines, linking to plaque vulnerability. Soluble TREM2 (sTREM2), shed from plaque macrophages, correlates with innate immunity upregulation and higher cardiovascular death risk (HR 2.37 in CAD cohorts). Impaired efferocytosis of apoptotic foam cells (via CD147 inhibition of GAS6 or PI3K-Akt-mTOR blockade) leads to necrotic debris accumulation, perpetuating inflammation. Vitamin D signaling via VDR suppresses NF-κB and cytokines (e.g., IL-6, TNF-α), offering protective effects, though deficiency accelerates CHD progression.

Advanced Stages: Smooth Muscle Cell Involvement and Plaque Formation/Instability

Vascular smooth muscle cells (VSMCs) migrate from the media to the intima, undergoing phenotypic switching from contractile to synthetic states via NLRP3 activation and miRNAs (e.g., miR-221/222 promoting proliferation, miR-146a inhibiting it). They produce extracellular matrix (ECM) proteins for fibrous cap formation but also contribute to calcification and neointimal hyperplasia. Proprotein convertase subtilisin/kexin type 9 (PCSK9) accumulates in plaques, degrading LDL receptors and enhancing monocyte infiltration, worsening lesions in aged models. Aging impairs VSMC mitophagy, elevating parkin and ROS, while oscillatory shear stress promotes carotid-like lesions in coronary analogs.

Plaques evolve into advanced lesions with necrotic cores from foam cell apoptosis/necrosis, thin fibrous caps (<65 μm), and intraplaque hemorrhage from hypoxia-induced angiogenesis (VEGF-A). Inflammation drives instability via matrix metalloproteinases (MMP9) degrading ECM, upregulated in stenotic regions by NF-κB and polymorphisms (e.g., rs3918249). In CHD, vulnerable coronary plaques (high macrophage content, low collagen) rupture in proximal, non-stenotic areas, triggering thrombosis via exposed tissue factor and procoagulants. TET2 mutations and UA elevate instability through ferroptosis and thinner caps, while NETs and angiogenesis exacerbate hemorrhage. Optical coherence tomography reveals UA-linked features like wider lipid arcs and calcification.

Recent Insights and Therapeutic Targets in CHD

Emerging insights highlight sex differences in genetic mechanisms, with understudied pathways like PDGFD promoting SMC transition to proinflammatory phenotypes in CAD. Omics data from cellular models reveal epigenetic regulators (e.g., miR-204 downregulating SR-A/CD36) and mitochondrial ROS in pyroptosis. For CHD, intravascular imaging (IVUS, OCT, NIRS) guides PCI to target vulnerable plaques, reducing MI risk.

Therapeutics target molecular nodes: IL-1β blockade (canakinumab) reduces events without lipid changes; XOR inhibitors (e.g., uricase) mitigate UA/ROS; miR-33 antagonists enhance efflux and regression; PCSK9 inhibitors stabilize plaques. KCa3.1 channel blockers reduce ROS/SMC proliferation, while purinergic modulators (e.g., P2X7 antagonists) curb leukocyte adhesion. Anti-inflammatory strategies like sTREM2 targeting and vitamin D supplementation show promise, bridging basic mechanisms to interventional cardiology for CHD prevention. Ongoing trials emphasize personalized approaches based on plaque molecular profiles.