Clinical and Preclinical Use of LOX-1-Specific Antibodies in Diagnostics and Therapeutics

Siqueira, Jullyana de Souza; Zani, Izma Abdul; Russell, David; Wheatcroft, Stephen; Ponnambalam, Sreenivasan; Homer‐Vanniasinkam, Shervanthi

doi:10.1007/s12265-015-9655-z

Cited by 13 publications

(13 citation statements)

References 62 publications

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“…LOX-1 is expressed on endothelial cells, smooth muscle cells and macrophages and is related to the development of atherosclerosis and other cardiovascular diseases. In addition, LOX-1 acts physiologically as an inducer of apoptosis, reactive oxygen species and proin ammatory cytokines [22][23][24]. We also found that LOX-1 was expressed in microglial cells, the resident brain macrophages, in the nHIE rat model (unpublished data).…”

Section: Introductionmentioning

confidence: 55%

LOX-1 Mediates Inflammatory Activation of Microglial Cells Through the p38-MAPK/NF-κB Pathways Under Hypoxic-Ischemic Conditions

Itoh¹,

Aoki²,

Akamatsu³

et al. 2020

Preprint

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Background: Microglial cells play an important role in the immune system in the brain. Activated microglial cells are not only injurious but also neuroprotective. We confirmed marked lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) expression in microglial cells in pathological lesions in the neonatal hypoxic-ischemic encephalopathy model brain. LOX-1 is known to be an activator of cytokines and chemokines through intracellular pathways. Here, we investigated a novel role of LOX-1 in microglial cells under hypoxic and ischemic conditions. Methods: We isolated primary rat microglial cells from 3-day-old Sprague-Dawley rat brains and confirmed that the isolated cells showed more than 98% Iba-1 positive with immunocytochemistry. We performed oxygen glucose deprivation (OGD) treatment of primary rat microglial cells as an in vitro model of nHIE. Then, we evaluated the expression levels of LOX-1, cytokines and chemokines with or without siRNA and inhibitors, compared with no OGD-treated cells. In addition, we analyzed reactive oxygen species and cell viability.Results: We found that defects in oxygen and nutrition induced LOX-1 expression and led to the production of inflammatory mediators, such as the cytokines IL-1β, IL-6 and TNF-α, the chemokines CCL2, CCL5 and CCL3 and reactive oxygen/nitrile species. Then, the LOX-1 signal transduction pathway was blocked by inhibitors, LOX-1 siRNA, the p38-MAPK inhibitor SB203580 and the NF-κB inhibitor BAY11-7082 suppressed the production of the inflammatory mediators. Moreover, we demonstrated that LOX-1 in microglial cells was autonomously overexpressed by positive feedback of the intracellular LOX-1 pathway. Conclusion: The hypoxic/ischemic conditions of microglial cells induced LOX-1 expression and activated immune system. We revealed one of the LOX-1 signaling pathways in microglia and provide a hint of a new treatment strategy for nHIE. It was speculated that Microglial cells are known to contribute to various neurological diseases. Hypoxic and ischemic brain injuries result in lifelong neurological and mental deficiency. LOX-1 and its related molecules or chemicals may be major therapeutic candidates.

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Section: Introductionmentioning

confidence: 55%

LOX-1 Mediates Inflammatory Activation of Microglial Cells Through the p38-MAPK/NF-κB Pathways Under Hypoxic-Ischemic Conditions

Itoh¹,

Aoki²,

Akamatsu³

et al. 2020

Preprint

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“…SR-E1 (LOX-1) является ключевым рецептором для oxLDL на эндотелиоцитах и сосудистых миоцитах. Высокая концентрация oxLDL, а также ROS и некоторых цитокинов (TNFα, TGF-β) провоцирует повышенную экспрессию LOX-1 на этих клетках [38]. В свою очередь, задействование LOX-1 запускает генерацию ROS за счет активации NADPH-зависимых оксидаз с последующей стимуляцией редокс-зависимых белков, таких как MAPK (p38, ERK1/2, JNK) и NF-κB, а также способствует биосинтезу многих белков, участвующих в атерогенезе [145].…”

Section: класс D представлен единственным рецептором Sr-d1 (Cd68)unclassified

“…В свою очередь, задействование LOX-1 запускает генерацию ROS за счет активации NADPH-зависимых оксидаз с последующей стимуляцией редокс-зависимых белков, таких как MAPK (p38, ERK1/2, JNK) и NF-κB, а также способствует биосинтезу многих белков, участвующих в атерогенезе [145]. Кроме того, взаимодействие LOX-1 с oxLDL может запустить в клетках процесс апоптоза и повреждение эндотелиальной выстилки [38,145]. В свою очередь, секреция эндотелием ROS способствует образованию в крови oxLDL, что в совокупности приводит к формированию порочного патогенетического круга и прогрессированию атеросклероза.…”

Section: класс D представлен единственным рецептором Sr-d1 (Cd68)unclassified

“…Патогенез метаболического синдрома связан с развитием хронического воспаления низкой интенсивности (системного паравоспаления), преимущественно развивающегося в факультативно гликолизирующих тканях, прежде всего в печени и жировом депо. Этот процесс характеризуется умеренными проявлениями системной воспалительной реакции, включая острофазный ответ печени, а также инсулинорезистентностью, гапатозом, эндотелиозом, саркопенией, ожирением [38,62,171]. При прогрессировании инсулинорезистентности метаболический синдром трансформируется в сахарный диабет 2-го типа.…”

Section: Sr при развитии метаболического синдрома и диабета 2-го типаunclassified

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Physiological and pathogenic role of scavenger receptors in humans

et al. 2020

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The scavenger receptors (SRs)) include > 30 different molecules structurally classified into 11 classes (A to L). They are expressed mostly on stromal macrophages, and their expression may be augmented in direct dependence with concentrations of their ligands. The SRs are heterogenous by their structure, however, being common in their functional potential. E.g., different SR classes may participate in absorption of modified low-density lipoproteins and glycated proteins, apoptotic and ageing cells, altered erythrocytes and platelets, like as a big variety of other endogenous ligands from metabolic and cellular “trash”. A common property of SRs is their participation in removal of small pathogen amounts from blood circulation, regulation of cell and tissue stress responses, ability to form complicated receptor complexes with other receptor types including integrins and toll-like receptors. Opposite to classic pattern-recognizing receptors, the SR involvement does not always elicit a pronounced cellular activation and development of pro-inflammatory cellular stress. The SR functional effects provide interactions between different physiological events and immune system, including the processes of neuroendocrine and metabolic regulation. These mechanisms provide both homeostatic stability and, likewise, act at the border of normal and pathological conditions, i.e., participating in pathogenesis of transitional processes, e.g., physiological ageing. Moreover, the SR-associated processes represent a key pathogenetic factor in different somatic diseases, e.g., those associated with low-intensity chronic inflammation, including obesity, type 2 diabetes, atherosclerosis, arterial hypertension, various neurodegenerative disorders. Similarly, the SRs are involved into the processes of cancer transformation and antitumor response, different processes of classical inflammation, from antigen presentation to the morphofunctional T cell and macrophage polarization in the inflammation foci and immunocompetent organs. SR are playing a controversial role in development of acute systemic inflammation, the main reason for lethal outcomes in the intensive care wards. Targeted effects upon the SRs represent a promising approach when treating a broad variety of diseases, whereas detection of membrane-bound and soluble SR forms could be performed by means of diagnostic and monitoring techniques in many human disorders.

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“…LOX-1 targeting in atherosclerosis attracts much interest, due to its proatherogenic properties [ 157 ]. In vitro studies show that blocking LOX-1 reduces the proapoptotic effects of oxLDL; transgenic animal studies indicate that OLR1/LDLR double-null mice exhibit reduced atherosclerotic plaque burden in coronary arteries [ 158 , 159 ].…”

Section: Srs As Therapeutic Targets In Cvdmentioning

confidence: 99%

Scavenger Receptors as Biomarkers and Therapeutic Targets in Cardiovascular Disease

Cuthbert

Shaik

Harrison

et al. 2020

Cells

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The process of atherosclerosis leads to the formation of plaques in the arterial wall, resulting in a decreased blood supply to tissues and organs and its sequelae: morbidity and mortality. A class of membrane-bound proteins termed scavenger receptors (SRs) are closely linked to the initiation and progression of atherosclerosis. Increasing interest in understanding SR structure and function has led to the idea that these proteins could provide new routes for cardiovascular disease diagnosis, management, and treatment. In this review, we consider the main classes of SRs that are implicated in arterial disease. We consider how our understanding of SR-mediated recognition of diverse ligands, including modified lipid particles, lipids, and carbohydrates, has enabled us to better target SR-linked functionality in disease. We also link clinical studies on vascular disease to our current understanding of SR biology and highlight potential areas that are relevant to cardiovascular disease management and therapy.

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Clinical and Preclinical Use of LOX-1-Specific Antibodies in Diagnostics and Therapeutics

Cited by 13 publications

References 62 publications

LOX-1 Mediates Inflammatory Activation of Microglial Cells Through the p38-MAPK/NF-κB Pathways Under Hypoxic-Ischemic Conditions

LOX-1 Mediates Inflammatory Activation of Microglial Cells Through the p38-MAPK/NF-κB Pathways Under Hypoxic-Ischemic Conditions

Physiological and pathogenic role of scavenger receptors in humans

Scavenger Receptors as Biomarkers and Therapeutic Targets in Cardiovascular Disease

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