Lectin-type oxidized LDL receptor-1 as a potential therapeutic target for cerebral cavernous malformations treatment.

Introduction: Cerebral cavernous malformations (CCMs) are pathologic lesions comprised of clusters of thin-walled capillaries characterized by abnormal proliferation, angiogenesis, and bleeding secondary to somatic or germline mutations in endothelial cells. CCMs can cause headaches, seizures and/or neurological defects. There is a clinical need to develop better tools to detect CCMs and follow their progression in conjunction with the current use of neuroimaging techniques. Here we present data supporting the utility of LOX-1 (lectin-type oxidized LDL receptor 1), a 50 kDa transmembrane protein implicated in endothelial cell dysfunction and ischemia, as a putative biomarker for CCM. Methods: CCM urine samples (n = 23) were collected from pediatric CCM patients. Matched healthy controls (n = 24) were collected from pediatric patients with either Chiari I malformation or fatty filum terminale, and otherwise normal findings. All samples were collected with patient/family consent and institutional review board approval.Samples were analyzed with Olink Proteomic Proximity Extension Assay (PEA). Differences in expression for 2,925 unique proteins were quantified between healthy control urine samples and CCM urine samples. The results were normalized, validated, and analyzed for demographic bias. In addition to urine samples, CCM tissue from patients was harvested and used to create primary cell lines for in vitro analysis of LOX-1 expression, in addition to immunofluorescence of lesional tissue excised at surgery. Results: ANOVA analysis of the CCM urine samples showed a statistically significant increase in LOX-1 compared to the control samples, with CCM patients exhibiting a > 5-fold increase in urinary expression. Corroborating these elevated levels of circulating marker, analysis of source tissue from surgically resected CCMs revealed that LOX-1 is increased in both CCM patient cavernoma primary cell lines and operative specimens. Conclusion: LOX-1 is involved with pathways implicated in CCM pathogenesis and our data here reveals that LOX-1 expression is significantly elevated in CCM patients as compared to matched healthy control individuals, including both source tissue from surgically excised CCMs and in analysis of samples collected from outside of the central nervous system, particularly urine. This proof-of-principle data suggests that LOX-1 may have potential utility as a target for CCM treatment and supports further investigation related to its potential mechanistic impact on CCM pathogenesis.

The Role of Natural Low Molecular Weight Dicarbonyls in Atherogenesis and Diabetogenesis.

This review summarises the data from long-term experimental studies and literature data on the role of oxidatively modified low-density lipoproteins (LDL) in atherogenesis and diabetogenesis. It was shown that not "oxidized" (lipoperoxide-containing) LDL, but dicarbonyl-modified LDL are atherogenic (actively captured by cultured macrophages with the help of scavenger receptors), and also cause expression of lectin like oxidized low density lipoprotein receptor 1 (LOX-1) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1 (NOX-1) genes in endotheliocytes, which stimulate apoptosis and endothelial dysfunction. The obtained data allowed us to justify new approaches to pharmacotherapy of atherosclerosis and diabetes mellitus.

Chelerythrine ameliorates Aspergillus fumigatus keratitis through suppressing the LOX-1/p38 MAPK signaling pathway.

PURPOSE: Aspergillus fumigatus (A. fumigatus) keratitis is a type of infectious corneal disease that significantly impairs vision. The objective of this study is to evaluate the therapeutic potential of chelerythrine (CHE) on A. fumigatus keratitis. METHODS: The antifungal activity of CHE was assessed through various tests including the minimum inhibitory concentration test, scanning electron microscopy, transmission electron microscopy, propidium iodide uptake test and plate count. Neutrophil infiltration and activity were assessed using immunofluorescence staining and the myeloperoxidase test. RT-PCR, western blotting assay, and ELISA were performed to measure the expression levels of proinflammatory cytokines (IL-1ß and IL-6), NF-E2-related factor (Nrf2), heme oxygenase-1 (HO-1), and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), as well as to determine the ratio of phosphorylated-p38 (p-p38) mitogen-activated protein kinase (MAPK) to p38 MAPK. RESULTS: In vitro, CHE inhibited the growth of A. fumigatus conidia, reduced fungal hyphae survival, and prevented fungal biofilm formation. In vivo, CHE reduced the severity of A. fumigatus keratitis and exhibited an excellent anti-inflammatory effect by blocking neutrophil infiltration. Furthermore, CHE decreased the expression levels of proinflammatory cytokines and LOX-1 at both mRNA and protein levels, while also decreasing the p-p38 MAPK/p38 MAPK ratio. Additionally, CHE increased the expression levels of Nrf2 and HO-1. CONCLUSION: CHE provides protection against A. fumigatus keratitis through multiple mechanisms, including reducing fungal survival, inducing anti-inflammatory effects, enhancing Nrf2 and HO-1 expression, and suppressing the signaling pathway of LOX-1/p38 MAPK.

Elevated levels of oxLDL and LOX-1: Implications for schizophrenia pathophysiology.

Inflammation and oxidative stress are both considered to be factors in the etiopathogenesis of schizophrenia. LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1) and ox-LDL (oxidized low-density lipoprotein) have been reported to be active in neuroinflammation pathways in which they are involved in oxidative stress and inflammation. However, its relationship with schizophrenia is unclear. This study aimed to assess the potential connection between serum ox-LDL and LOX-1 levels in schizophrenia patients, their unaffected first-degree relatives, and healthy controls. The study comprised 63 schizophrenia patients, 57 first-degree relatives, and 63 healthy controls who were age, gender, and BMI-matched. Serum ox-LDL and LOX-1 levels were measured. PANSS was used to assess the severity of the disease. Levels of both ox-LDL and LOX-1 were markedly elevated in individuals diagnosed with schizophrenia when compared to both their relatives and a control group. While ox-LDL levels were significantly higher in relatives of patients compared to controls, there was no significant difference between relatives of patients and control groups for LOX-1 levels. Significant correlations were observed between PANNS general and total and ox-LDL levels and PANNS negative and LOX-1 levels. The relationship between ox-LDL and LOX-1 and schizophrenia is quite limited in the literature and is a new field of study. Future studies are needed to evaluate their role in etiopathogenesis.

High-fat-diet-induced obesity promotes simultaneous progression of lung cancer and atherosclerosis in apolipoprotein E-knockout mice.

Background: Clinical studies have shown that atherosclerotic cardiovascular disease and cancer often co-exist in the same individual. The present study aimed to investigate the role of high-fat-diet (HFD)-induced obesity in the coexistence of the two diseases and the underlying mechanism in apolipoprotein E-knockout (ApoE-/-) mice. Methods: Male ApoE-/- mice were fed with a HFD or a normal diet (ND) for 15 weeks. On the first day of Week 13, the mice were inoculated subcutaneously in the right axilla with Lewis lung cancer cells. At Weeks 12 and 15, serum lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and vascular endothelial growth factor levels were measured by enzyme-linked immunosorbent assay, and blood monocytes and macrophages were measured by fluorescence-activated cell sorting. At Week 15, the volume and weight of the local subcutaneous lung cancer and metastatic lung cancer and the amount of aortic atherosclerosis were measured. Results: At Week 15, compared with mice in the ND group, those in the HFD group had a larger volume of local subcutaneous cancer (p = 0.0004), heavier tumors (p = 0.0235), more metastatic cancer in the lungs (p < 0.0001), a larger area of lung involved in metastatic cancer (p = 0.0031), and larger areas of atherosclerosis in the aorta (p < 0.0001). At Week 12, serum LOX-1, serum vascular endothelial growth factor, and proportions of blood monocytes and macrophages were significantly higher in the HFD group than those in the ND group (p = 0.0002, p = 0.0029, p = 0.0480, and p = 0.0106, respectively); this trend persisted until Week 15 (p = 0.0014, p = 0.0012, p = 0.0001, and p = 0.0204). Conclusions: In this study, HFD-induced obesity could simultaneously promote progression of lung cancer and atherosclerosis in the same mouse. HFD-induced upregulation of LOX-1 may play an important role in the simultaneous progression of these two conditions via the inflammatory response and VEGF.

Differential Effects of LOX-1 Inhibition on Aortic Structure and Posterior Cerebral Artery Structure and Function in an Experimental Model of Preeclampsia.

Preeclampsia is a hypertensive disorder of pregnancy marked by vascular dysfunction, large artery stiffness, and excess oxidized low-density lipoprotein (oxLDL). oxLDL activates oxidative stress pathways which contribute to arterial stiffness through interaction with the lectin-like oxLDL receptor 1 (LOX-1). Increased vascular stiffness is associated with higher pulse wave velocity and downstream microvasculature damage. Here we evaluated the ability of LOX-1 inhibition (LOX-1i) to prevent large artery structural and microvascular structural and functional changes via assessment of the descending thoracic aorta (DTAo) and posterior cerebral arteries (PCA) in a high cholesterol model of preeclampsia. Adult female Sprague Dawley normal late-pregnant (LP) and experimentally preeclamptic (ePE, high cholesterol diet d7-19) animals underwent intraperitoneal (i.p.) implantation of a mini-osmotic pump at d12 containing LOX-1 neutralizing antibodies (ePE + LOX-1i, n = 7) or goat IgG as vehicle control (LP + IgG, n = 8 and ePE + IgG, n = 8). Animals were studied at d19. DTAos and PCAs were removed for histologic assessment and isolated vessel experiments, respectively. Fetuses and placentas were weighed individually. Plasma was analyzed for markers of oxidative stress. ePE + IgG DTAo elastin content (an indirect metric of stiffness) was not significantly different from the LP + IgG group. Nonetheless, trending elastin break and sinuosity data (higher number of breaks and lower sinuosity in the ePE + IgG group compared to LP + IgG) suggested increased stiffness in this high cholesterol PE model. LOX-1i appeared to prevent a decrease in elastin. PCAs showed no structural changes with ePE or LOX-1i. ePE PCAs had increased reactivity to the nitric oxide donor sodium nitroprusside and decreased tone that was unaffected by LOX-1i. ePE animals had increased plasma oxLDL and 3-nitrotyrosine that was unaffected by LOX-1i. Taken together, LOX-1i may improve large artery stiffness without mitigation of the oxidative stress or cerebral microvascular dysfunction seen in ePE. Understanding these mechanisms is important in abating the long-term risks of preeclampsia.

LOX-1 in Cardiovascular Disease: A Comprehensive Molecular and Clinical Review.

LOX-1, ORL-1, or lectin-like oxidized low-density lipoprotein receptor 1 is a transmembrane glycoprotein that binds and internalizes ox-LDL in foam cells. LOX-1 is the main receptor for oxidized low-density lipoproteins (ox-LDL). The LDL comes from food intake and circulates through the bloodstream. LOX-1 belongs to scavenger receptors (SR), which are associated with various cardiovascular diseases. The most important and severe of these is the formation of atherosclerotic plaques in the intimal layer of the endothelium. These plaques can evolve into complicated thrombi with the participation of fibroblasts, activated platelets, apoptotic muscle cells, and macrophages transformed into foam cells. This process causes changes in vascular endothelial homeostasis, leading to partial or total obstruction in the lumen of blood vessels. This obstruction can result in oxygen deprivation to the heart. Recently, LOX-1 has been involved in other pathologies, such as obesity and diabetes mellitus. However, the development of atherosclerosis has been the most relevant due to its relationship with cerebrovascular accidents and heart attacks. In this review, we will summarize findings related to the physiologic and pathophysiological processes of LOX-1 to support the detection, diagnosis, and prevention of those diseases.

Radical Oxygen Species, Oxidized Low-Density Lipoproteins, and Lectin-like Oxidized Low-Density Lipoprotein Receptor 1: A Vicious Circle in Atherosclerotic Process.

Atherosclerosis is a complex condition that involves the accumulation of lipids and subsequent plaque formation in the arterial intima. There are various stimuli, cellular receptors, and pathways involved in this process, but oxidative modifications of low-density lipoprotein (ox-LDL) are particularly important in the onset and progression of atherosclerosis. Ox-LDLs promote foam-cell formation, activate proinflammatory pathways, and induce smooth-muscle-cell migration, apoptosis, and cell death. One of the major receptors for ox-LDL is LOX-1, which is upregulated in several cardiovascular diseases, including atherosclerosis. LOX-1 activation in endothelial cells promotes endothelial dysfunction and induces pro-atherogenic signaling, leading to plaque formation. The binding of ox-LDLs to LOX-1 increases the generation of reactive oxygen species (ROS), which can induce LOX-1 expression and oxidize LDLs, contributing to ox-LDL generation and further upregulating LOX-1 expression. This creates a vicious circle that is amplified in pathological conditions characterized by high plasma levels of LDLs. Although LOX-1 has harmful effects, the clinical significance of inhibiting this protein remains unclear. Further studies both in vitro and in vivo are needed to determine whether LOX-1 inhibition could be a potential therapeutic target to counteract the atherosclerotic process.

Plumbagin inhibits fungal growth, HMGB1/LOX-1 pathway and inflammatory factors in A. fumigatus keratitis.

To investigate the anti-inflammatory and antifungal effects of plumbagin (PL) in Aspergillus fumigatus (A. fumigatus) keratitis, the minimum inhibitory concentration (MIC), time-killing curve, spore adhesion, crystal violet staining, calcium fluoride white staining, and Propidium Iodide (PI) staining were employed to assess the antifungal activity of PL in vitro against A. fumigatus. The cytotoxicity of PL was assessed using the Cell Counting Kit-8 (CCK8). The impact of PL on the expression of HMGB1, LOX-1, TNF-α, IL-1ß, IL-6, IL-10 and ROS in A. fumigatus keratitis was investigated using RT-PCR, ELISA, Western blot, and Reactive oxygen species (ROS) assay. The therapeutic efficacy of PL against A. fumigatus keratitis was assessed through clinical scoring, plate counting, Immunofluorescence and Hematoxylin-Eosin (HE) staining. Finally, we found that PL inhibited the growth, spore adhesion, and biofilm formation of A. fumigatus and disrupted the integrity of its cell membrane and cell wall. PL decreased IL-6, TNF-α, and IL-1ß levels while increasing IL-10 expression in fungi-infected mice corneas and peritoneal macrophages. Additionally, PL significantly attenuated the HMGB1/LOX-1 pathway while reversing the promoting effect of Boxb (an HMGB1 agonist) on HMGB1/LOX-1. Moreover, PL decreased the level of ROS. In vivo, clinical scores, neutrophil recruitment, and fungal burden were all significantly reduced in infected corneas treated with PL. In summary, the inflammatory process can be inhibited by PL through the regulation of the HMGB-1/LOX-1 pathway. Simultaneously, PL can exert antifungal effects by limiting fungal spore adhesion and biofilm formation, as well as causing destruction of cell membranes and walls.

The association between oxidized low-density lipoprotein and cancer: An emerging targeted therapeutic approach?

Lipids play an important role in varying vital cellular processes including cell growth and division. Elevated levels of low-density lipoprotein (LDL) and oxidized-LDL (ox-LDL), and overexpression of the corresponding receptors including LDL receptor (LDLR), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), and cluster of differentiation 36 (CD36), have shown strong correlations with different facets of carcinogenesis including proliferation, invasion, and angiogenesis. Furthermore, a high serum level of LOX-1 is considered as a poor prognostic factor in many types of cancer including colorectal cancer. Ox-LDL could contribute to cancer progression and metastasis through endothelial-to-mesenchymal transition (EMT) and autophagy. Thus, many studies have shed light on the significant role of ox-LDL as a potential therapeutic target for cancer therapy. In various repurposing approaches, anti-dyslipidemia agents, phytochemicals, autophagy modulators as well as recently developed ldl-like nanoparticles have been investigated as potential tumor therapeutic agents by targeting oxidized-LDL/LOX-1 pathways. Herein, we reviewed the role of oxidized-LDL and LOX-1 in cancer progression, invasion, metastasis, and also cancer-associated angiogenesis. Moreover, we addressed therapeutic utility of several compounds that proved to be capable of targeting the metabolic moieties in cancer. This review provides insights on the potential impact of targeting LDL and ox-LDL in cancer therapy and their future biomedical implementations.

Role of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 in Inflammation and Pathogen-Associated Interactions.

BACKGROUND: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is known as a major receptor for oxidized low-density lipoproteins (oxLDL) and plays a significant role in the genesis of atherosclerosis. Recent research has shown its involvement in cancer, ischemic stroke, and diabetes. LOX-1 is a C-type lectin receptor and is involved in the activation of immune cells and inflammatory processes. It may further interact with pathogens, suggesting a role in infections or the host's response. SUMMARY: This review compiles the current knowledge of potential implications of LOX-1 in inflammatory processes and in host-pathogen interactions with a particular emphasis on its regulatory role in immune responses. Also discussed are genomic and structural variations found in LOX-1 homologs across different species as well as potential involvements of LOX-1 in inflammatory processes from the angle of different cell types and organ-specific interactions. KEY MESSAGES: The results presented reveal both similar and different structures in human and murine LOX-1 and provide clues as to the possible origins of different modes of interaction. These descriptions raise concerns about the suitability, particularly of mouse models, that are often used in the analysis of its functionality in humans. Further research should also aim to better understand the mostly unknown binding and interaction mechanisms between LOX-1 and different pathogens. This pursuit will not only enhance our understanding of LOX-1 involvement in inflammatory processes but also identify potential targets for immunomodulatory approaches.

LOX-1 regulation of H-type vascular endothelial cell regeneration in hyperglycemia.

AIMS: Diabetic osteoporosis (DOP) is the most common secondary form of osteoporosis. Diabetes mellitus affects bone metabolism; however, the underlying pathophysiological mechanisms remain unclear. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) expression is upregulated in conditions characterized by vascular injury, such as atherosclerosis, hypertension, and diabetes. Additionally, Notch, HIF-1α, and VEGF are involved in angiogenesis and bone formation. Therefore, we aimed to investigate the expression of Notch, HIF-1α, and VEGF in the LOX-1 silencing state. METHODS: Rat bone H-type vascular endothelial cells (THVECs) were isolated and cultured in vitro. Cell identification was performed using immunofluorescent co-expression of CD31 and Emcn. Lentiviral silencing vector (LV-LOX-1) targeting LOX-1 was constructed using genetic recombination technology and transfected into the cells. The experimental groups included the following: NC group, HG group, LV-LOX-1 group, LV-CON group, HG + LV-LOX-1 group, HG + LV-CON group, HG + LV-LOX-1 + FLI-06 group, HG + LV-CON + FLI-06 group, HG + LV-LOX-1 + LW6 group, and HG + LV-CON + LW6 group. The levels of LOX-1, Notch, Hif-1α, and VEGF were detected using PCR and WB techniques to investigate whether the expression of LOX-1 under high glucose conditions has a regulatory effect on downstream molecules at the gene and protein levels, as well as the specific molecular mechanisms involved. RESULTS: High glucose (HG) conditions led to a significant increase in LOX-1 expression, leading to inhibition of angiogenesis, whereas silencing LOX-1 can reverse this phenomenon. Further analysis reveals that changes in LOX-1 will promote changes in Notch/HIF-1α and VEGF. Moreover, Notch mediates the activation of HIF-1α and VEGF. CONCLUSIONS: The activation of LOX-1 and the inhibition of Notch/HIF-1α/VEGF in THVECs are the main causes of DOP. These findings contribute to our understanding of the pathogenesis of DOP and offer a novel approach for preventing and treating osteoporosis.

Associations of CKIP-1 and LOX-1 polymorphisms with the risk of type 2 diabetes mellitus with hypertension among Chinese adults.

AIMS: Type 2 diabetes mellitus (T2DM) and hypertension are common high-incidence diseases, closely related, and have common pathogenic basis such as oxidative stress. Casein kinase 2 interacting protein-1 (CKIP-1) and low-density lipoprotein receptor (LOX-1) are considered to be important factors affect the level of oxidative stress in the body. The main purpose of this study was to explore the relationship between CKIP-1 (rs6693817 A > T, rs2306235 C > G) and LOX-1 (rs1050283 G > A, rs11053646 C > G) polymorphisms and the risk of hypertension and diabetes, and try to find new candidate genes for diabetes and diabetes with hypertension etiology in Chinese population. METHODS: 574 T2DM patients and 597 controls frequently matched by age and sex were selected for genotyping of CKIP-1 (rs6693817 A > T, rs2306235 C > G) and LOX-1 gene (rs1050283 G > A, rs11053646 C > G). Logistic regression was used to analyze the correlation between different genotypes and the risk of T2DM and T2DM with hypertension, and the results were expressed as odds ratio (OR) and 95% confidence interval (95% CI). RESULTS: We found that the risk of T2DM in the AA + AT genotype of rs6693817 was higher than that in the TT genotype in Chinese population (OR = 1.318, 95%CI: 1.011-1.717, P = 0.041), and the difference was still significant after adjustment (OR = 1.370, 95%CI: 1.043-1.799, Padjusted = 0.024), the difference of heterozygotes (AT vs TT: OR = 1.374, 95%CI: 1.026-1.840, Padjusted = 0.033) was statistically significant. But after Bonferroni correction, the significance of the above sites disappeared. And rs6693817 was associated with the risk of T2DM combined with hypertension before and after adjustment in dominant model (OR = 1.424, 95% CI: 1.038-1.954, P = 0.028; OR = 1.460, 95% CI: 1.057-2.015, Padjusted = 0.021, respectively) and in heterozygote model (OR = 1.499, 95% CI: 1.069-2.102, P = 0.019; OR = 1.562, 95% CI: 1.106-2.207, Padjusted = 0.011, respectively). However, only the statistical significance of the heterozygous model remained after Bonferroni correction. rs2306235, rs1050283 and rs11053646 were not significantly correlated with T2DM and T2DM combined with hypertension risk (P > 0.05). CONCLUSIONS: The results suggest that CKIP-1 rs6693817 is related to the susceptibility of Chinese people to T2DM with hypertension, providing a new genetic target for the treatment of diabetes with hypertension with in the future.

High-fat diet causes endothelial dysfunction in the mouse ophthalmic artery.

Obesity is a significant health concern that leads to impaired vascular function and subsequent abnormalities in various organs. The impact of obesity on ocular blood vessels, however, remains largely unclear. In this study, we examined the hypothesis that obesity induced by high-fat diet produces vascular endothelial dysfunction in the ophthalmic artery. Mice were subjected to a high-fat diet for 20 weeks, while age-matched controls were maintained on a standard diet. Reactivity of isolated ophthalmic artery segments was assessed in vitro. Reactive oxygen species (ROS) were quantified in cryosections by dihydroethidium (DHE) staining. Redox gene expression was determined in ophthalmic artery explants by real-time PCR. Furthermore, the expression of nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2), the receptor for advanced glycation end products (RAGE), and of the lectin-like oxidized low-density-lipoprotein receptor-1 (LOX-1) was determined in cryosections using immunofluorescence microscopy. Ophthalmic artery segments from mice on a high-fat diet exhibited impaired vasodilation responses to the endothelium-dependent vasodilator acetylcholine, while endothelium-independent responses to nitroprusside remained preserved. DHE staining intensity in the vascular wall was notably stronger in mice on a high-fat diet. Messenger RNA expression for NOX2 was elevated in the ophthalmic artery of mice subjected to high fat diet. Likewise, immunostainings revealed increased expression of NOX2 and of RAGE, but not of LOX-1. These findings suggest that a high-fat diet triggers endothelial dysfunction by inducing oxidative stress in the ophthalmic artery via involvement of RAGE and NOX2.

Knockdown of LOX-1 ameliorates bone quality and generation of type H blood vessels in diabetic mice.

Our previous studies have shown that lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) is expressed in liver sinusoidal endothelial cells, and oxidized low-density lipoprotein induces liver sinusoidal dysfunction and defenestration through the LOX-1/ROS/NF-kB pathway, revealing that LOX-1 can mediate liver sinusoidal barrier function, involved in the regulation of non-alcoholic fatty liver disease. Here, we investigated whether, in the context of bone metabolic diseases, LOX-1 could affect bone quality and type H blood vessels in diabetic mice. We used db/db mice as model and found that LOX-1 knockdown can ameliorate bone quality and type H blood vessel generation in db/db mice. This further verifies our hypothesis that LOX-1 is involved in the regulation of bone quality and type H blood vessel homeostasis, thus inhibiting osteoporosis progression in db/db mice.

Elevated soluble LOX-1 predicts risk of first-time myocardial infarction.

BACKGROUND: There is an unmet clinical need for novel therapies addressing the residual risk in patients receiving guideline preventive therapy for coronary heart disease. Experimental studies have identified a pro-atherogenic role of the oxidized LDL receptor LOX-1. We investigated the association between circulating soluble LOX-1 (sLOX-1) and the risk for development of myocardial infarction. METHODS: The study subjects (n = 4658) were part of the Malmö Diet and Cancer study. The baseline investigation was carried out 1991-1994 and the incidence of cardiovascular events monitored through national registers during a of 19.5 ± 4.9 years follow-up. sLOX-1 and other biomarkers were analyzed by proximity extension assay and ELISA in baseline plasma. RESULTS: Subjects in the highest tertile of sLOX-1 had an increased risk of myocardial infarction (hazard ratio (95% CI) 1.76 (1.40-2.21) as compared with those in the lowest tertile. The presence of cardiovascular risk factors was related to elevated sLOX-1, but the association between sLOX-1 and risk of myocardial infarction remained significant when adjusting for risk factors. CONCLUSIONS: In this prospective population study we found an association between elevated sLOX-1, the presence of carotid disease and the risk for first-time myocardial infarction. Taken together with previous experimental findings of a pro-atherogenic role of LOX-1, this observation supports LOX-1 inhibition as a possible target for prevention of myocardial infarction.

Activation of the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) represents a possible target for treatment of the residual inflammatory risk in cardiovascular patients on guideline therapy.Having high levels of soluble LOX-1, a marker of cellular LOX-1 activation, is associated with an increased risk for development of myocardial infarction and heart failure.sLOX-1 levels correlated with major cardiovascular risk factors and biomarkers reflecting LDL oxidation.

Wall Teichoic Acid Mediates Staphylococcus aureus Binding to Endothelial Cells via the Scavenger Receptor LOX-1.

The success of Staphylococcus aureus as a major cause for endovascular infections depends on effective interactions with blood-vessel walls. We have previously shown that S. aureus uses its wall teichoic acid (WTA), a surface glycopolymer, to attach to endothelial cells. However, the endothelial WTA receptor remained unknown. We show here that the endothelial oxidized low-density lipoprotein receptor 1 (LOX-1) interacts with S. aureus WTA and permits effective binding of S. aureus to human endothelial cells. Purified LOX-1 bound to isolated S. aureus WTA. Ectopic LOX-1 expression led to increased binding of S. aureus wild type but not of a WTA-deficient mutant to a cell line, and LOX-1 blockage prevented S. aureus binding to endothelial cells. Moreover, WTA and LOX-1 expression levels correlated with the efficacy of the S. aureus-endothelial interaction. Thus, LOX-1 is an endothelial ligand for S. aureus, whose blockage may help to prevent or treat severe endovascular infections.

Lipids and lipoproteins may play a role in the neuropathology of Alzheimer's disease.

Alzheimer's disease (AD) and other classes of dementia are important public health problems with overwhelming social, physical, and financial effects for patients, society, and their families and caregivers. The pathophysiology of AD is poorly understood despite the extensive number of clinical and experimental studies. The brain's lipid-rich composition is linked to disturbances in lipid homeostasis, often associated with glucose and lipid abnormalities in various neurodegenerative diseases, including AD. Moreover, elevated low-density lipoprotein (LDL) cholesterol levels may be related to a higher probability of AD. Here, we hypothesize that lipids, and electronegative LDL (L5) in particular, may be involved in the pathophysiology of AD. Although changes in cholesterol, triglyceride, LDL, and glucose levels are seen in AD, the cause remains unknown. We believe that L5-the most electronegative subfraction of LDL-may be a crucial factor in understanding the involvement of lipids in AD pathology. LDL and L5 are internalized by cells through different receptors and mechanisms that trigger separate intracellular pathways. One of the receptors involved in L5 internalization, LOX-1, triggers apoptotic pathways. Aging is associated with dysregulation of lipid homeostasis, and it is believed that alterations in lipid metabolism contribute to the pathogenesis of AD. Proposed mechanisms of lipid dysregulation in AD include mitochondrial dysfunction, blood-brain barrier disease, neuronal signaling, inflammation, and oxidative stress, all of which lead ultimately to memory loss through deficiency of synaptic integration. Several lipid species and their receptors have essential functions in AD pathogenesis and may be potential biomarkers.

LOX-1 variants modulate the severity of cardiovascular disease: state of the art and future directions.

Atherosclerosis is one of the major causes of cerebral infarction and many other ischemic cardio-cerebrovascular diseases. Although large randomized clinical trials have highlighted the impressive benefits of lipid-lowering therapies, the 50-70% of patients who have achieved their lipid-lowering goal remain at high cardiovascular disease risk. For this reason, there is a need to investigate other markers of atherosclerosis progression. LOX-1 is a scavenger receptor that accepts oxidized low-density lipoproteins as major ligand and internalizes it by endocytosis favoring its retention in subendothelial layer and triggering a wide variety of proatherogenic events. However, other factors such as cytokines, shear stress, and advanced glycation end-products can upregulate LOX-1. LOX-1 is encoded by the OLR1 gene, located in the p12.3-p13 region of chromosome 12. OLR1 gene has different isoforms induced by splicing, or single-nucleotide polymorphisms (SNPs). According to some authors, the expression of these isoforms induces a different effect on atherosclerosis and cardiovascular disease. In particular, LOXIN, an isoform lacking part of the functional domain, exerts an important role in atherosclerosis protection. In other cases, studies on SNPs showed an association with more severe forms, like in the case of 3'UTR polymorphisms. The knowledge of these variants can give rise to the development of new preventive therapies and can lead to the identification of subjects at greater risk of cardiovascular event. In this review, we reported the state of the art regarding SNPs with known effects on OLR1 splicing and how LOX-1 variants modulate the severity of cardiovascular disease.

"Affimer" synthetic protein scaffolds block oxidized LDL binding to the LOX-1 scavenger receptor and inhibit ERK1/2 activation.

In multicellular organisms, a variety of lipid-protein particles control the systemic flow of triacylglycerides, cholesterol, and fatty acids between cells in different tissues. The chemical modification by oxidation of these particles can trigger pathological responses, mediated by a group of membrane proteins termed scavenger receptors. The lectin-like oxidized low-density lipoprotein (LOX-1) scavenger receptor binds to oxidized low-density lipoprotein (oxLDL) and mediates both signaling and trafficking outcomes. Here, we identified five synthetic proteins termed Affimers from a phage display library, each capable of binding recombinant LOX-1 extracellular (oxLDL-binding) domain with high specificity. These Affimers, based on a phytocystatin scaffold with loop regions of variable sequence, were able to bind to the plasma membrane of HEK293T cells exclusively when human LOX-1 was expressed. Binding and uptake of fluorescently labeled oxLDL by the LOX-1-expressing cell model was inhibited with subnanomolar potency by all 5 Affimers. ERK1/2 activation, stimulated by oxLDL binding to LOX-1, was also significantly inhibited (p < 0.01) by preincubation with LOX-1-specific Affimers, but these Affimers had no direct agonistic effect. Molecular modeling indicated that the LOX-1-specific Affimers bound predominantly via their variable loop regions to the surface of the LOX-1 lectin-like domain that contains a distinctive arrangement of arginine residues previously implicated in oxLDL binding, involving interactions with both subunits of the native, stable scavenger receptor homodimer. These data provide a new class of synthetic tools to probe and potentially modulate the oxLDL/LOX-1 interaction that plays an important role in vascular disease.