Endothelial overexpression of LOX-1 increases plaque formation and promotes atherosclerosis in vivo

Akhmedov, Alexander; Rozenberg, Izabela; Paneni, Francesco; Camici, Giovanni G.; Shi, Yi; Doerries, Carola; Śledzińska, Anna; Mocharla, Pavani; Berndt, Alexander; Lohmann, Christine; Stein, Sokrates; Lukowicz, Tobias von; Kurrer, Michael; Borén, Jan; Becher, Burkhard; Tanner, Felix C.; Landmesser, Ulf; Matter, Christian M.; Lüscher, Thomas F.

doi:10.1093/eurheartj/eht532

Cited by 87 publications

(70 citation statements)

References 28 publications

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“…LOX-1 is the main OxLDL receptor of endothelial cells (10). Endothelial overexpression of LOX-1 has been found to increase plaque formation and promote atherosclerosis in vivo (21). Upregulation of LOX-1 contributes to palmitic acid-induced uptake of OxLDL in macrophage cells (22).…”

Section: Discussionmentioning

confidence: 99%

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

Yang

Bian

Zhang

et al. 2015

Molecular Medicine Reports

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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.

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Section: Discussionmentioning

confidence: 99%

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

Yang

Bian

Zhang

et al. 2015

Molecular Medicine Reports

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“…Activation of endothelial cells by oxLDL through LOX-1 upregulation may be a key event in HT development, the most important risk factor for atherosclerosis. 5,25 Akhmedov et al 27 showed that endothelial LOX-1 was sufficient for atherosclerosis development in vivo. Endothelial-specific LOX-1 overexpression enhanced aortic oxLDL levels, thereby favoring endothelial dysfunction, vascular inflammation and plaque formation.…”

Section: Discussionmentioning

confidence: 99%

Endothelial damage in white coat hypertension: role of lectin-like oxidized low-density lipoprotein-1

Yavuzer

Cengiz

et al. 2014

J Hum Hypertens

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The aims of this study included an examination of soluble lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (sLOX-1) levels in hypertensive (HT) patients. Another aim examined sLOX-1 associations with oxidized LDL (oxLDL), nitric oxide synthase (eNOS) and nitric oxide (NOx). A final aim was to compare these parameters between HT patients, white-coat hypertensive (WCH) patients and healthy controls. The three groups, HT, WCH and controls, were comprised of 35 patients each. sLOX-1 and oxLDL levels were significantly increased in WCH and HT patients compared with controls. The eNOS activation was significantly lower in HT than in the control group. sLOX-1 and oxLDL levels were significantly negatively correlated with eNOS levels in the WCH and HT groups. Carotid intima-media thickness (CIMT) measurements were significantly higher in the WCH and HT groups compared with controls. There was a significant positive correlation between CIMT and sLOX-1 and oxLDL; however, there was a negative correlation with eNOS in WCH. Regression analysis revealed that sLOX-1 was the variable that had a significant effect on blood pressure (P<0.001, odds ratio (95% confidence interval=23.273 (5.843-92.688)). A possible endothelial impairment may act as a cardiovascular risk factor in WCH. Necessary measures should be considered in terms of atherosclerosis risk with HT, especially in early identification of endothelial damage by looking at sLOX-1 levels. We believe sLOX-1 levels are strong biomarkers for determining early endothelial damage in HT, and especially in WCH patients.

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“…The results of gene knockout of SR-A, CD36, and LOX-1 in mice suggest that these oxidized LDL receptors promote atherosclerosis, at least in murine models [7][8][9][10][11], while conflicting results were reported regarding SR-A and CD36 [12,13].…”

Section: Understanding Atherothrombotic Diseases As Receptor-centric mentioning

confidence: 99%

LOX-1 in atherosclerotic disease

Sawamura

Wakabayashi

Okamura

2015

Clinica Chimica Acta

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Endothelial overexpression of LOX-1 increases plaque formation and promotes atherosclerosis in vivo

Abstract: Endothelial-specific LOX-1 overexpression enhanced aortic oxLDL levels, thereby favouring endothelial dysfunction, vascular inflammation and plaque formation. Thus, LOX-1 may serve as a novel therapeutic target for atherosclerosis.

Cited by 87 publications

References 28 publications

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

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

Endothelial damage in white coat hypertension: role of lectin-like oxidized low-density lipoprotein-1

LOX-1 in atherosclerotic disease

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