LOX-1 is implicated in oxidized low-density lipoprotein-induced oxidative stress of macrophages in atherosclerosis

Abstract

Abstract. Induction of oxidative stress has a causal role in atherosclerosis. The aim of the present study was to examine the role of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in oxidized low-density lipoprotein (OxLDL)-induced oxidative stress in atherosclerosis. Small interfering RNA (siRNA) technology was employed to decrease the expression of LOX-1 in mouse RAW264.7 macrophages and the effects of LOX-1 silencing on OxLDL-induced reactive oxygen species (ROS) generation and NADPH oxidase (NOX) expression were investigated. The in vivo effects of reducing LOX-1 were also examined in a mouse model (ApoE-/-) of high-fat diet-induced atherosclerosis. Compared with the control cells, OxLDL exposure led to a significant (P<0.05) increase in the intracellular levels of malondialdehyde and ROS and a significant decrease in the activity of superoxide dismutase. Delivery of LOX-1-targeting siRNA significantly (P<0.05) reversed the alterations in oxidative stress parameters induced by OxLDL. LOX-1 silencing downregulated the expression of NOX2, Rac1, p47phox and p22phox and impaired the activation of mitogen-activated protein kinases in OxLDL-treated cells. Adenoviral delivery of LOX-1 siRNA caused a significant increase in the size of the fibrous cap and a decrease in the macrophage content in lesions, compared with the control mice. Western blot analysis demonstrated that the protein expression levels of NOX1, Rac1, p47phox and p22phox in aortic lesions were significantly lower in the LOX-1 siRNA group than in the control group. LOX-1 is implicated in OxLDL-induced oxidative stress of macrophages in atherosclerosis, which in part, involves the regulation of NADPH oxidases.

Effects of crocin and saffron aqueous extract on gene expression of SIRT1, AMPK, LOX1, NF‐κB, and MCP‐1 in patients with coronary artery disease: A randomized placebo‐controlled clinical trial

“…Increase in proatherogenic stimuli such as ox‐LDL, high sensitivity C‐reactive protein (CRP), and homocysteine leads to overexpression of LOX1 in atherosclerotic lesions (Gao & Geng, ). In human studies, it has been proved that there are a close association between LOX1 expression and ROS generation in human vascular smooth muscle cells and macrophages (Dai et al, ; Yang et al, ). Recent finding demonstrated that dietary antioxidants could prevent the ox‐LDL and tumor necrosis factor‐α (TNF‐α)‐induced LOX1 expression and oxidative stress, key events that lead to mitogen‐activated protein kinase/extracellular signal‐regulated kinase (ERK)1/2 and NF‐κB activation linked to endothelial dysfunction (Caliceti et al, ).…”

Targeting LOX‐1 in atherosclerosis and vasculopathy: current knowledge and future perspectives

“…Excessive production of ROS occurs in response to ox‐LDL treatment. However, LOX‐1 siRNA attenuates NADPH oxidase activity and MAPK pathway–dependent ROS production . LOX‐1 also inhibits macrophage migration and promotes foam cell formation induced by various proatherogenic treatments .…”

Sarpogrelate and rosuvastatin synergistically ameliorate aortic damage induced by hyperlipidemia in apolipoprotein E‑deficient mice

“…2B). The interaction between oxidized (ox)-LDL and LOX-1 results in ox-LDL uptake by macrophages and foam cell transformation (24,25). Collectively, these results indicate that sarpogrelate and rosuvastatin can synergistically prevent aortic damage induced by hyperlipidemia and reverse atherosclerosis, which may be associated with the regulation of LOX-1 expression.…”