Mechanism of Hypercholesterolemia-Induced Atherosclerosis

Abstract

Hypercholesterolemia is involved in the development of atherosclerosis and is a risk factor for coronary artery disease, stroke, and peripheral vascular disease. This paper deals with the mechanism of development of hypercholesterolemic atherosclerosis. Hypercholesterolemia increases the formation of numerous atherogenic biomolecules including reactive oxygen species (ROS), proinflammatory cytokines [interleukin (IL)-1, IL-2, IL-6, IL-8, tumor necrosis factor-alpha (TNF- $\alpha$ )], expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, monocyte chemoattractant protein-1 (MCP-1), granulocyte macrophage-colony stimulating factor (GM-CSF) and numerous growth factors [insulin-like growth factor-1 (IGF-1), platelet-derived growth factor-1 (PDGF-1) and transforming growth factor-beta (TGF- $\beta$ )]. ROS mildly oxidizes low-density lipoprotein-cholesterol (LDL-C) to form minimally modified LDL (MM-LDL) which is further oxidized to form oxidized LDL (OX-LDL). Hypercholesterolemia also activates nuclear factor-kappa-B (NF- $\kappa$ B). The above atherogenic biomolecules are involved in the development of atherosclerosis which has been described in detail. Hypercholesterolemia also assists in the development of atherosclerosis through AGE (advanced glycation end-products)-RAGE (receptor for AGE) axis and C-reactive protein (CRP). Hypercholesterolemia is associated with increases in AGE, oxidative stress [AGE/sRAGE (soluble receptor for AGE)] and C-reactive protein, and decreases in the sRAGE, which are known to be implicated in the development of atherosclerosis. In conclusion, hypercholesterolemia induces atherosclerosis through increases in atherogenic biomolecules, AGE-RAGE axis and CRP.

Keywords: C-reactive protein; advanced glycation end products; atherogenic biomolecules; atherosclerosis; cell adhesion molecules; cytokines; hypercholesterolemia; nuclear factor-kappa B; reactive oxygen species.

Fig. 1.

Effects of hypercholesterolemia on atherogenic biomolecules. Hypercholesterolemia increases the generation of ROS (reactive oxygen species) and cytokines [interleukin (IL)-1, IL-2, IOl-6, IL-8, tumor necrosis factor-alpha (TNF-$\alpha$)], and activates nuclear factor-kappa B (NF-$\kappa$B). Cytokines generate ROS and increase the expression and release of cell adhesion molecules [intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin]. ROS increase the expression and release of cell adhesion molecules, growth factors [insulin-like growth factor-1 (IGF-1), transforming growth factor-beta (TGF-$\beta$)], and increases oxidation of low-density lipoprotein cholesterol (LDL-C) to form minimally modified LDL (MM-LDL) which is further oxidized to form maximally oxidized-LDL (OX-LDL). MM-LDL produces monocyte chemoattractant protein-1 (MCP-1) and monocyte colony stimulating factor (M-CSF) from endothelial cells. OX-LDL assist in migration of monocytes in subendothelial space and formation of foam cells. All the above biomolecules are involved in the development of atherosclerosis. $\leftrightarrows$, rightward and leftward arrow; $\uparrow$, increase.

Fig. 2.

Schematic diagram of mechanism of hypercholesterolemia-induced atherosclerosis. ROS, reactive oxygen species; ICAM-1, intercellular adhesion molecule-1; VCAM-1, vascular cell adhesion molecule-1; EC, endothelial cell; LDL, low-density lipoprotein; MM-LDL, minimally modified LDL; OX-LDL, maximally oxidized LDL; MCP-1, monocyte chemoattractant protein; VSMC, vascular smooth muscle cell; MC-SF, monocyte colony stimulating factor; TYM, tissue macrophage; PDGF, platelet-derived growth factor; IGF-1, insulin-like growth factor-1; TGF-$\beta$, and transforming growth factor-$\beta$. $\uparrow$, increase; $\leftrightarrows$ , rightward and leftward arrow.