LOX-1 The Multifunctional Receptor Underlying Cardiovascular Dysfunction

Ogura, Sayoko; Kakino, Akemi; Sato, Yuko; Fujita, Yoshiko; Iwamoto, Seiichi; Otsui, Kazunori; Yoshimoto, Ryo; Sawamura, Tatsuya

doi:10.1253/circj.cj-09-0587

Cited by 102 publications

(41 citation statements)

References 73 publications

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“…Thus, in low-ESS arterial regions where the endothelium was more receptive to circulating cholesterol, intimal lipid accumulation was determined by the magnitude of hypercholesterolemia. While we found no cholesterol effect on VCAM-1 or MCP-1 expression, our finding of greater inflammation in low-ESS segments exposed to higher- vs. relatively lower cholesterol might relate to an enhanced inflammatory response to greater lipid accumulation [36], and to the induction of LOX-1 – a multifunctional receptor known to promote plaque inflammation [37,38]. …”

Section: Discussionmentioning

confidence: 99%

Synergistic effect of local endothelial shear stress and systemic hypercholesterolemia on coronary atherosclerotic plaque progression and composition in pigs

Koskinas

Chatzizisis

Papafaklis

et al. 2013

International Journal of Cardiology

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Background Systemic risk factors and local hemodynamic factors both contribute to coronary atherosclerosis, but their possibly synergistic inter-relationship remains unknown. The purpose of this natural history study was to investigate the combined in-vivo effect of varying levels of systemic hypercholesterolemia and local endothelial shear stress (ESS) on subsequent plaque progression and histological composition. Methods Diabetic, hyperlipidemic swine with higher systemic total cholesterol (TC) (n=4) and relatively lower TC levels (n=5) underwent three-vessel intravascular ultrasound (IVUS) at 3–5 consecutive time-points in-vivo. ESS was calculated serially using computational fluid dynamics. 3-D reconstructed coronary arteries were divided into 3mm-long segments (n=595), which were stratified according to higher vs. relatively lower TC and low (<1.2 Pa) vs. higher local ESS (≥1.2 Pa). Arteries were harvested at 9 months, and a subset of segments (n=114) underwent histopathologic analyses. Results Change of plaque volume (ΔPV) by IVUS over time was most pronounced in low-ESS segments from higher-TC animals. Notably, higher-ESS segments from higher-TC animals had greater ΔPV compared to low-ESS segments from lower-TC animals (p<0.001). The time-averaged ESS in segments that resulted in significant plaque increased with increasing TC levels (slope: 0.24 Pa/100mg/dl; r=0.80; p<0.01). At follow-up, low-ESS segments from higher-TC animals had the highest mRNA levels of lipoprotein receptors and inflammatory mediators and, consequently, the greatest lipid accumulation and inflammation. Conclusions This study redefines the principle concept that “low” ESS promotes coronary plaque growth and vulnerability by demonstrating that: (i.) the pro-atherogenic threshold of low ESS is not uniform, but cholesterol-dependent; and (ii.) the atherogenic effects of local low ESS are amplified, and the athero-protective effects of higher ESS may be outweighed, by increasing cholesterol levels. Intense hypercholesterolemia and very low ESS are synergistic in favouring rapid atheroma progression and high-risk composition.

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Section: Discussionmentioning

confidence: 99%

Synergistic effect of local endothelial shear stress and systemic hypercholesterolemia on coronary atherosclerotic plaque progression and composition in pigs

Koskinas

Chatzizisis

Papafaklis

et al. 2013

International Journal of Cardiology

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“…LOX-1 can be up-regulated by many factors such as oxLDL, AngII, shear stress, and advanced glycation end products (AGEs) [21]. The up-regulation or activation of LOX-1 is thought to play important roles in pathogenesis of cardiovascular diseases, such as atherosclerosis, coronary artery diseases, and myocardial infarction [4]. Factors which suppress LOX-1 are thought to be beneficial to the cardiovascular systems.…”

Section: Discussionmentioning

confidence: 99%

“…Lectin-like low-density lipoprotein receptor 1 (LOX-1) is a multifunctional receptor participating in cardiovascular dysfunction [4]. It was first identified to be a receptor for oxLDL in endothelial cells [5].…”

Section: Introductionmentioning

confidence: 99%

Protective Effects of Let-7a and Let-7b on Oxidized Low-Density Lipoprotein Induced Endothelial Cell Injuries

et al. 2014

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Lectin-like low-density lipoprotein receptor 1 (LOX-1) is a receptor for oxidized low density lipoprotein (oxLDL) in endothelial cells. The activation of LOX-1 by oxLDL stimulates the apoptosis and dysfunction of endothelial cells, and contributes to atherogenesis. However, the regulatory factors for LOX-1 are still unclear. MicroRNAs are small, endogenous, non-coding RNAs that regulate gene expressions at a post-transcriptional level. The let-7 family is the second microRNA been discovered, which plays important roles in cardiovascular diseases. Let-7a and let-7b were predicted to target LOX-1 3′-UTR and be highly expressed in endothelial cells. The present study demonstrated that LOX-1 was a target of let-7a and let-7b. They inhibited the expression of LOX-1 by targeting the positions of 310-316 in LOX-1 3′-UTR. Over-expression of let-7a and let-7b inhibited the oxLDL-induced endothelial cell apoptosis, NO deficiency, ROS over-production, LOX-1 upregulation and endothelial nitric oxide synthase (eNOS) downregulation. Moreover, we found that oxLDL treatment induced p38MAPK phosphorylation, NF-κB nuclear translocation, IκB degradation and PKB dephosphorylation. Let-7a or let-7b over-expression attenuated these alterations significantly. The present study may provide a new insight into the protective properties of let-7a and let-7b in preventing the endothelial dysfunction associated with cardiovascular disease, such as atherosclerosis.

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“…LOX-1 consists of a short N-terminus cytoplasmic domain, transmembrane domain, neck domain, and a C-type lectin-like domain [23]. It is synthesized as a 40-kDa precursor protein with N -linked high mannose-type carbohydrate, which is further glycosylated and processed into a 50-kDa mature form [24].…”

Section: Introductionmentioning

confidence: 99%

LOX-1 in atherosclerosis: biological functions and pharmacological modifiers

Ogura

Chen

et al. 2012

Cell. Mol. Life Sci.

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Lectin-like oxidized LDL (oxLDL) receptor-1 (LOX-1, also known as OLR-1), is a class E scavenger receptor that mediates the uptake of oxLDL by vascular cells. LOX-1 is involved in endothelial dysfunction, monocyte adhesion, the proliferation, migration, and apoptosis of smooth muscle cells, foam cell formation, platelet activation, as well as plaque instability; all of these events are critical in the pathogenesis of atherosclerosis. These LOX-1-dependent biological processes contribute to plaque instability and the ultimate clinical sequelae of plaque rupture and life-threatening tissue ischemia. Administration of anti-LOX-1 antibodies inhibits atherosclerosis by decreasing these cellular events. Over the past decade, multiple drugs including naturally occurring antioxidants, statins, antiinflammatory agents, antihypertensive and antihyperglycemic drugs have been demonstrated to inhibit vascular LOX-1 expression and activity. Therefore, LOX-1 represents an attractive therapeutic target for the treatment of human atherosclerotic diseases. This review aims to integrate the current understanding of LOX-1 signaling, regulation of LOX-1 by vasculoprotective drugs, and the importance of LOX-1 in the pathogenesis of atherosclerosis.

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LOX-1 The Multifunctional Receptor Underlying Cardiovascular Dysfunction

Cited by 102 publications

References 73 publications

Synergistic effect of local endothelial shear stress and systemic hypercholesterolemia on coronary atherosclerotic plaque progression and composition in pigs

Synergistic effect of local endothelial shear stress and systemic hypercholesterolemia on coronary atherosclerotic plaque progression and composition in pigs

Protective Effects of Let-7a and Let-7b on Oxidized Low-Density Lipoprotein Induced Endothelial Cell Injuries

LOX-1 in atherosclerosis: biological functions and pharmacological modifiers

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