Abstract
Oxidized low-density lipoprotein (OxLDL) contributes to the atherosclerotic plaque formation and progression by several mechanisms, including the induction of endothelial cell activation and dysfunction, macrophage foam cell formation, and smooth muscle cell migration and proliferation. Vascular wall cells express on their surface several scavenger receptors that mediate the cellular effects of OxLDL. The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the main OxLDL receptor of endothelial cells, and it is expressed also in macrophages and smooth muscle cells. LOX-1 is almost undetectable under physiological conditions, but it is upregulated following the exposure to several proinflammatory and proatherogenic stimuli and can be detected in animal and human atherosclerotic lesions. The key contribution of LOX-1 to the atherogenic process has been confirmed in animal models; LOX-1 knockout mice exhibit reduced intima thickness and inflammation and increased expression of protective factors; on the contrary, LOX-1 overexpressing mice present an accelerated atherosclerotic lesion formation which is associated with increased inflammation. In humans, LOX-1 gene polymorphisms were associated with increased susceptibility to myocardial infarction. Inhibition of the LOX-1 receptor with chemicals or antisense nucleotides is currently being investigated and represents an emerging approach for controlling OxLDL-LOX-1 mediated proatherogenic effects.
Highlights
Atherosclerosis is a chronic inflammatory vascular disease, having as ultimate outcome the atheromatous plaque, a focal lesion located within the intima of large and medium sized arteries [1, 2]
lipoprotein receptor-1 (LOX-1) is mainly localized in caveolae/lipid rafts in the plasma membrane; its function is modulated by the cholesterol content of membrane: cholesterol depletion induces the mislocalization of LOX-1, which results in a more diffuse distribution of the receptor in the plasma membrane and in a marked reduction of LOX-1-mediated Oxidized low density lipoprotein (LDL) (OxLDL) binding and uptake [15]
OxLDL activates caspase-9 and caspase-3 in endothelial cells (ECs) and induces the release of mitochondrial activators of caspases, while reducing the expression of the antiapoptotic proteins B-cell lymphoma 2 (Bcl-2) and cellular inhibitor of apoptosis protein 1 (c-IAP-1) [38]. These effects are mediated by LOX1, as pretreatment of cells with antisense to LOX-1 messenger RNA (mRNA) significantly decreases OxLDL-induced activation of caspases as well as the percentage of apoptotic cells [38]. These findings indicate that OxLDL through its receptor LOX-1 modulates activity and expression of relevant players in apoptosis
Summary
Atherosclerosis is a chronic inflammatory vascular disease, having as ultimate outcome the atheromatous plaque, a focal lesion located within the intima of large and medium sized arteries [1, 2]. LOX-1 is mainly localized in caveolae/lipid rafts (cholesterol-enriched membrane microdomains) in the plasma membrane; its function is modulated by the cholesterol content of membrane: cholesterol depletion induces the mislocalization of LOX-1, which results in a more diffuse distribution of the receptor in the plasma membrane (without a reduction of the amount of receptor exposed on the cell surface) and in a marked reduction of LOX-1-mediated OxLDL binding and uptake [15]. Other stimuli Homocysteine Free radicals distribution of LOX-1 in specific membrane microdomains is essential for an efficient interaction with OxLDL and for the internalization of OxLDL-LOX-1 complexes
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