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Title: The LOX-1 scavenger receptor in atherosclerosis, angiogenesis and glucose metabolism
Author: Mughal, Nadeem Akhter
ISNI:       0000 0004 5372 191X
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2015
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The lectin-like oxidised low-density lipoprotein receptor-1 (LOX-1) is a class E scavenger receptor expressed on vascular cells including endothelium, smooth muscle and macrophages. LOX-1 binds to a variety of particles including oxidised low-density lipoprotein (OxLDL). At the cellular level, binding of LOX-1 to OxLDL appears to initiate endothelial dysfunction, apoptosis and foam cell formation, thereby linking the receptor to the pathogenesis of atherosclerosis. Experimental findings in pro-atherosclerotic LDLR-null mice reveal a significant reduction in plaque distribution with concomitant LOX-1 knockout, but only following a highly aggressive cholesterol-rich diet. We wanted to assess the impact of LOX-1 deletion in the more widely used ApoE-null model on a standard pro-atherogenic diet. Contrary to previous reports, we observed that LOX-1 knockout significantly increased aortic plaque coverage and was associated with higher levels of total cholesterol and LDL. The influence of LOX-1 in glucose metabolism and homeostasis is largely unknown. Here, we show that knockout of the receptor results in glucose intolerance and increased insulin sensitivity. This effect is due to decreased levels of circulating plasma insulin potentially caused by a lack of phosphorylated Akt. LOX-1 is reported to play a role in angiogenesis through its downstream effect on vascular endothelial growth factor (VEGF). SiRNA knockdown of LOX-1 did not affect proliferation but reduced the migratory response of human umbilical vein endothelial cells (HUVECs). Sprouting from aortic rings was increased in LOX-1 knockout mice but no difference was observed in femoral artery endothelial regeneration. This work has shed light on a potential role for LOX-1 in clearing OxLDL from the bloodstream, thereby conferring an atheroprotective effect. The receptor also appears to regulate insulin production, glucose metabolism and angiogenic sprouting. Further work is needed to clarify the mechanisms for these findings that question the validity of targeting LOX-1 as a therapeutic avenue for peripheral arterial disease.
Supervisor: Homer-Vanniasinkam, Shervanthi ; Ponnambalam, Sreenivasan ; Russell, David Sponsor: Circulation Foundation
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available