Lipoprotein trafficking in vascular cells: Molecular Trojan horses and cellular saboteurs
During the pathogenesis of atherosclerosis, inflammatory cells such as the monocyte-derived macrophage accumulate in the vessel wall where they release cytokines. Initially, cytokines may assist in CE removal of lipoprotein-derived cholesterol/CE hydrolysis to clear intracellular lipid. When plasma levels of LDL become elevated, the vessel wall becomes lipid-engorged over time because it is unable to traffick the large amounts of endocytosed LDL-CE from the cell. In addition, lipoprotein entrapment by the extracellular matrix can lead to the progressive oxidation of LDL because of the action of lipoxygenases, reactive oxygen species, peroxynitrite, and/or myeloperoxidase. A range of oxidized LDL species is thus generated, ultimately resulting in their delivery to vascular cells through several families of scavenger receptors (Fig 1). These molecular Trojan horses and cellular saboteurs once formed or deposited in the cell can contribute to, and participate in, formation of macrophage- and smooth muscle-derived foam cells. A lipid-enriched fatty streak along the vessel wall can ensue. In addition to foam cell development, products of LDL peroxidation may activate endothelial cells, increase smooth muscle mitogenesis, or induce apoptosis because of the effects of oxysterols and products of lipid peroxidation (Fig 1). Because antioxidant defenses may be limited in the microenvironment of the cell or within LDL, the oxidation process continues to progress. Enzymes associated with HDL such as PAF acetylhydrolase and paraoxonase can participate in the elimination of biologically active lipids, but diminished cellular antioxidant activity coupled with low levels of HDL may allow acceleration of the clinical course of vascular disease. There is still much to be learned about how modified LDL initiate cellular signals that lead to inflammation, mitosis, or cholesterol accumulation. The present challenges include elucidation of the key signaling events that regulate lipoprotein-derived cholesterol trafficking in the vessel wall, which can impact on the pathogenesis of vascular disease.