CD36 and Atherosclerosis
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Abstract:
CD36,belongs to class B scavenger receptor family,is a transmembrane glycoprotein expressed on various tissues.On macrophages,CD36 is a major scavenger receptor for oxidized low density lipoprotein(ox-LDL).In addition to its significant roles in atherosclerosis,CD36 also exerts multiple roles including promoting coagulation and monocytes accumulation,pro-inflammatory and antioxidant roles,etc.The expression of CD36 is highly regulated by many factors,and plays an important role in the development of atherosclerosis.Keywords:
CD36
Scavenger Receptor
Foam cell
Scavenger
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Abstract Atherosclerosis is a serious public health concern. Excessive inflammatory responses of vascular cells are considered a pivotal pathogenesis mechanism underlying atherosclerosis development. It is known that Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signalling plays an important role in atherosclerosis progression. Protein inhibitor of activated STAT3 (PIAS3) is the key negative regulator of JAK/STAT3 signalling. However, its effect on atherogenesis is unknown. Here, we observed that PIAS3 levels are reduced in atherosclerotic lesions and that PIAS3 expression decreases in conjunction with increases in interleukin-6 expression and atherosclerosis severity. Oxidized low-density lipoprotein (ox-LDL), an atherogenic stimulus, reduced PIAS3 expression, an effect that may be attributed to nitric oxide synthesis upregulation. In turn, PIAS3 overexpression effectively suppressed ox-LDL-induced inflammation, lipid accumulation and vascular smooth muscle cell proliferation. These results indicate that PIAS3 is a critical repressor of atherosclerosis progression. The findings of this study have contributed to our understanding on the pathogenesis of atherosclerosis and have provided us with a potential target through which we can inhibit atherosclerosis-related cellular responses.
Foam cell
Apolipoprotein E
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There is increasing clinical evidence that phospholipid oxidation products (Ox-PL) play a role in atherosclerosis. This review focuses on the mechanisms by which Ox-PL interact with endothelial cells, monocyte/macrophages, platelets, smooth muscle cells, and HDL to promote atherogenesis. In the past few years major progress has been made in identifying these mechanisms. It has been recognized that Ox-PL promote phenotypic changes in these cell types that have long-term consequences for the vessel wall. Individual Ox-PL responsible for specific cellular effects have been identified. A model of the configuration of bioactive truncated Ox-PL within membranes has been developed that demonstrates that the oxidized fatty acid moiety protrudes into the aqueous phase, rendering it accessible for receptor recognition. Receptors and signaling pathways for individual Ox-PL species are now determined and receptor independent signaling pathways identified. The effects of Ox-PL are mediated both by gene regulation and transcription independent processes. It has now become apparent that Ox-PL affects multiple genes and pathways, some of which are proatherogenic and some are protective. However, at concentrations that are likely present in the vessel wall in atherosclerotic lesions, the effects promote atherogenesis. There have also been new insights on enzymes that metabolize Ox-PL and the significance of these enzymes for atherosclerosis. With the knowledge we now have of the regulation and effects of Ox-PL in different vascular cell types, it should be possible to design experiments to test the role of specific Ox-PL on the development of atherosclerosis.
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Atherosclerosis has long been known to be a chronic inflammatory disease. In addition, there is intense oxidative stress in atherosclerosis resulting from an imbalance between the excess reactive oxygen species (ROS) generation and inadequate anti-oxidant defense forces. The excess of the oxidative forces results in the conversion of low-density lipoproteins (LDL) to oxidized LDL (ox-LDL), which is highly atherogenic. The sub-endothelial deposition of ox-LDL, formation of foamy macrophages, vascular smooth muscle cell (VSMC) proliferation and migration, and deposition of collagen are central pathophysiologic steps in the formation of atherosclerotic plaque. Ox-LDL exerts its action through several different scavenger receptors, the most important of which is LOX-1 in atherogenesis. LOX-1 is a transmembrane glycoprotein that binds to and internalizes ox-LDL. This interaction results in variable downstream effects based on the cell type. In endothelial cells, there is an increased expression of cellular adhesion molecules, resulting in the increased attachment and migration of inflammatory cells to intima, followed by their differentiation into macrophages. There is also a worsening endothelial dysfunction due to the increased production of vasoconstrictors, increased ROS, and depletion of endothelial nitric oxide (NO). In the macrophages and VSMCs, ox-LDL causes further upregulation of the LOX-1 gene, modulation of calpains, macrophage migration, VSMC proliferation and foam cell formation. Soluble LOX-1 (sLOX-1), a fragment of the main LOX-1 molecule, is being investigated as a diagnostic marker because it has been shown to be present in increased quantities in patients with hypertension, diabetes, metabolic syndrome and coronary artery disease. LOX-1 gene deletion in mice and anti-LOX-1 therapy has been shown to decrease inflammation, oxidative stress and atherosclerosis. LOX-1 deletion also results in damage from ischemia, making LOX-1 a promising target of therapy for atherosclerosis and related disorders. In this article we focus on the different mechanisms for regulation, signaling and the various effects of LOX-1 in contributing to atherosclerosis.
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Endothelial Dysfunction
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Abstract Atherosclerosis is a chronic inflammatory disease arising due to an imbalance in lipid metabolism and maladaptive immune response driven by the accumulation of cholesterol‐laden macrophages in the artery wall. Interactions between monocytes/macrophages and endothelial cells play an essential role in the pathogenesis of atherosclerosis. In our current study, nitric oxide synthase 1 (NOS1)‐derived nitric oxide (NO) has been identified as a regulator of macrophage and endothelial cell interaction. Oxidized LDL (OxLDL) activates NOS1, which results in the expression of CD40 ligand in macrophages. OxLDL‐stimulated macrophages produce some soluble factors which increase the CD40 receptor expression in endothelial cells. This increases the interaction between the macrophages and endothelial cells, which leads to an increase in the inflammatory response. Inhibition of NOS1‐derived NO might serve as an effective strategy to reduce foam cell formation and limit the extent of atherosclerotic plaque expansion.
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CD36
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Endothelial Dysfunction
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Scavenger receptors are membrane glycoproteins that bind diverse ligands including lipid particles, phospholipids, apoptotic cells and pathogens. LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1) is increasingly linked to atherosclerotic plaque formation. Transgenic mouse models for LOX-1 overexpression or gene knockout suggests that LOX-1 contributes to atherosclerotic plaque formation and progression. LOX-1 activation by oxidized LDL (low-density lipoprotein) binding stimulates intracellular signalling, gene expression and production of superoxide radicals. A key question is the role of leucocyte LOX-1 in pro-atherogenic lipid particle trafficking, accumulation and signalling leading to differentiation into foam cells, necrosis and plaque development. LOX-1 expression is elevated within vascular lesions and a serum soluble LOX-1 fragment appears diagnostic of patients with acute coronary syndromes. LOX-1 is increasingly viewed as a vascular disease biomarker and a potential therapeutic target in heart attack and stroke prevention.
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