What is the role of LDL cholesterol in the etiology of coronary artery atherosclerosis?

Updated: Apr 09, 2021
  • Author: Sandy N Shah, DO, MBA, FACC, FACP, FACOI; Chief Editor: Yasmine S Ali, MD, MSCI, FACC, FACP  more...
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Answer

The most atherogenic type of lipid is the low-density lipoprotein (LDL) component of total serum cholesterol. The endothelium's ability to modify lipoproteins may be particularly important in atherogenesis. LDLs appear to be modified by a process of low-level oxidation when bound to the LDL receptor, internalized, and transported through the endothelium. LDLs initially accrue in the subendothelial space and stimulate vascular cells to produce cytokines for recruiting monocytes, which causes further LDL oxidation. Extensively oxidized LDL (oxLDL), which is exceedingly atherogenic, is picked up by the scavenger receptors on macrophages, which absorb the LDL.

Cholesterol accumulation in macrophages is promoted by oxLDL; the macrophages then become foam cells. In addition, oxLDL enhances endothelial production of leukocyte adhesion molecules (ie, cytokines and growth factors that regulate SMC proliferation, collagen degradation, and thrombosis [eg, vascular cell adhesion molecule-1, intercellular cell adhesion molecule-1]).

Oxidized LDL inhibits nitric oxide synthase activity and increasing reactive oxygen species generation (eg, superoxide, hydrogen peroxide), thus reducing endothelium-dependent vasodilation. Moreover, oxLDL alters the SMC response to A-II stimulation and increasing vascular A-II concentrations. The SMCs that proliferate in the intima to form advanced atheromas are originally derived from the media. The theory that accumulation of SMCs in the intima represents the sine qua non of the lesions of advanced atherosclerosis is now widely accepted.

Substantial evidence suggests that oxLDL is the prominent component of atheromas. Antibodies against oxLDL react with atherosclerotic plaques, and plasma levels of immunoreactive altered LDL are greater in persons with AMI than in controls. Oxidative stress has therefore been recognized as the most significant contributor to atherosclerosis by causing LDL oxidation and increasing nitric oxide breakdown.


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