Lipoprotein oxidation in cardiovascular disease: chief culprit or innocent bystander?

Abstract

Oxidation of low-density lipoprotein (LDL) is thought to contribute to atherosclerosis and cardiovascular disease. Consistent with this idea, the antioxidant drug probucol reduces the risk of restenosis, a form of cardiovascular disease, in humans. However, a new study now suggests that the protective effect of probucol depends not on its ability to inhibit lipid oxidation, but on its ability to induce the stress-induced antiinflammatory enzyme heme oxygenase (HO)-1. This might explain why other antioxidants, such as vitamin E, fail to prevent cardiovascular disease in humans.

Figure 1.

Initiation and progression of atherosclerotic lesions. LDL enters the subendothelial space and is oxidized. Oxidized LDL (OxLDL) promotes monocyte adhesion to injured or inflamed epithelium and migration into the artery wall, where the cells differentiate into macrophages. OxLDL also binds to scavenger receptors on macrophages. This binding triggers uptake of OxLDL, converting macrophages into lipid-laden foam cells. Subsequently, smooth muscle cells migrate into the subendothelial space, where they accumulate and produce extracellular matrix, two important components of more advanced atherosclerotic lesions.

Figure 2.

Proposed pathways for the impact of probucol on the pathogenesis of vascular disease. (A) LDL in the intima of the artery wall is oxidized with the generation of proatherogenic lipid oxidation products (OxLDL). The phenol moiety of probucol blocks this process by acting as a scavenger of one-electron oxidants. (B) Vascular injury results in endothelial injury, smooth muscle cell (SMC) proliferation, and an influx of inflammatory cells and SMCs into the intima. Probucol induces the cellular expression of HO-1, presumably by cells of the artery wall. HO-1 reduces intimal hyperplasia and promotes tissue repair by several direct cellular actions. For example, the HO-1 product CO has been shown to inhibit endothelial cell (EC) apoptosis, prevent SMC proliferation, and inhibit macrophage production of inflammatory mediators, all of which may be important in vascular protection. Probucol may also react with two-electron oxidants that play a role in tissue injury.