Oxidized LDL Receptor-1 Research Articles

Double ‐ Stranded RNA Analog Poly I:C Enhances the Expression of Lectin‐Like Oxidized LDL Receptor‐1 in Macrophages: Role of ERK1/2 Signaling

We previously reported that bacterial lipopolysaccharide (LPS) enhanced the expression of lectin-like oxidized LDL receptor-1 (LOX-1) in macrophages through activation of the ERK1/2 signaling, thereby enhancing the cellular uptake of ox-LDL. Polyinosinic:polycytidylic acid (Poly I:C), a synthetic analog of double-stranded RNA (dsRNA), which activates various cell signaling via TLR3, has been shown to accelerate atherosclerotic lesions in multiple animal models. However, the underlying molecular mechanism mediating this response is obscure. Therefore, the present study aimed to investigate whether or not Poly I:C affects the expression of LOX-1 and explore the underlying molecular mechanisms. In RAW 264.7 macrophages, Poly I: C stimulation dose- and time-dependently enhanced the expression of LOX1. Although Poly I:C induced the activation of MAP kinases (p38, JNK1/2, ERK1/2), AP1 (c-FOS/JUN), and NF-kB signaling molecules, a specific ERK1/2 inhibitor (U0128) effectively inhibited the upregulation of LOX-1. Additionally, transient knockdown of ERK1/2 by small interference RNA prevented Poly I:C-induced overexpression of LOX1. Poly I:C stimulation augmented LOX-1 promoter activity, which is also inhibited by U0126 treatment. Similar results were also observed in human PMA-induced THP-1 human macrophages. Overall, we sought that Poly I:C, a viral mimic, upregulates the expression of LOX-1 through activation of the ERK1/2 signaling, highlighting a critical role of TLR3-mediated impaired LOX-1 signaling in the pathogenesis of atherosclerosis.

Emergence of immunosuppressive LOX-1+ PMN-MDSC in septic shock and severe COVID-19 patients with acute respiratory distress syndrome.

Myeloid‐derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells with immunosuppressive properties. In cancer patients, the expression of lectin‐type oxidized LDL receptor 1 (LOX‐1) on granulocytic MDSC identifies a subset of MDSC that retains the most potent immunosuppressive properties. The main objective of the present work was to explore the presence of LOX‐1+ MDSC in bacterial and viral sepsis. To this end, whole blood LOX‐1+ cells were phenotypically, morphologically, and functionally characterized. They were monitored in 39 coronavirus disease‐19 (COVID‐19, viral sepsis) and 48 septic shock (bacterial sepsis) patients longitudinally sampled five times over a 3 wk period in intensive care units (ICUs). The phenotype, morphology, and immunosuppressive functions of LOX‐1+ cells demonstrated that they were polymorphonuclear MDSC. In patients, we observed the significant emergence of LOX‐1+ MDSC in both groups. The peak of LOX‐1+ MDSC was 1 wk delayed with respect to ICU admission. In COVID‐19, their elevation was more pronounced in patients with acute respiratory distress syndrome. The persistence of these cells may contribute to long lasting immunosuppression leaving the patient unable to efficiently resolve infections.

Inhibition of the transient receptor potential vanilloid 3 channel attenuates carbon tetrachloride-induced hepatic fibrosis

Transient receptor potential vanilloid 3 (TRPV3) is a member of the TRP superfamily. Previous studies have demonstrated that TRPV3 is associated with myocardial fibrosis. However, the role of TRPV3 in hepatic fibrosis and its underlying mechanisms are still unclear. This study aimed to elucidate the underlying effects of TRPV3 on hepatic fibrosis at multiple biological levels. First, immunohistochemical staining was performed to examine TRPV3 expression in human hepatic cirrhosis tissues. Then, we established a CCl4-induced hepatic fibrosis mouse model. The TRPV3 selective agonist drofenine and its inhibitor, forsythoside B, were intraperitoneally injected to investigate the relationship between TRPV3 and liver fibrosis progression. Finally, in vitro studies were performed using hepatic stellate cells (HSCs) to discover the potential molecular biological mechanisms. Immunohistochemistry revealed TRPV3 overexpression in liver cirrhosis. In the liver fibrosis groups, TRPV3 inhibitor treatment significantly reduced liver fibrosis, while TRPV3 agonist exacerbated its progression. In HSCs, knocking down TRPV3 with siRNA impaired DNA synthesis and cell proliferation and increased cell apoptosis. Furthermore, we found that knockdown of TRPV3 could reduce the lectin like oxidized lowdensity lipoprotein receptor-1 (LOX-1) protein levels. Our research suggests that lower expression or functional levels of TRPV3 can ameliorate the inflammatory response and fibrotic tissue proliferation.

RAGE-MEDIATED CELLULAR SIGNALING IS TRIGGERED BY THE ALLOSTERIC ACTIVATION OF THE AT1 RECEPTOR

Objective: We recently identified the physical interaction of a pattern recognition receptor (PRR), lectin-like oxidized LDL receptor with the GPCR, angiotensin II type 1 receptor (AT1) whereby oxLDL allosterically activates AT1. In this study, we investigated if AT1 physically interacts with another PRR, the receptor for AGE (RAGE), and ligands of RAGE could allosterically activate AT1. Design and method: We used normal rat kidney epithelial cells (NRK52E) to investigate the interaction of the endogenous receptors. We also generated five different genetically-engineered CHO cells to individually analyze the G protein and β-arrestin pathways of AT1 activation; CHO cells expressing human RAGE (CHO-RAGE), CHO cells expressing both hRAGE and hAT1 (CHO-RAGE-AT1), CHO cells expressing both hRAGE and mutated hAT1 with impaired ability to activate G protein, and CHO cells expressing both hLOX-1 and mutated hAT1 with impaired ability to activate β-arrestin Results: In NRK52E, AGE-BSA provoked the activation of MAP kinase (ERK) that was inhibited by ARB or siRNA of AT1 or RAGE. Activation of NfκB and Epithelial mesanchmal transition induced by AGE-BSA was inhibited by ARBs as well as RAGE inhibitor. In genetically engineered CHO-cells, in situ PLA assay and immunoprecipitation confirmed the physical interaction of AT1 and RAGE on cellular membrane. HMGB1, a RAGE ligand induced Gαi-dependent inhibition of cAMP production only in the presence of both RAGE and AT1 with intact G protein binding. The effect of HMGB1 on cAMP content was abolished by ARB as well as RAGE inhibitor. HMGB1 did not induce the accumulation of IP1, a downstream of Gαq signaling, in CHO cells expressing both AT1 and RAGE. Real-time imaging of cellular membrane revealed that RAGE induced endocytosis of LOX-1 that depends on the intact β-arrestin pathway of AT1, and the phenomenon was not inhibited by ARB. Conclusions: RAGE ligands mediates cellular signaling via a physical interaction between RAGE and AT1. The activation of AT1 by RAGE ligands is distinct from that by angiotensin II in terms of selective G protein activation and the effect of ARB on G protein pathway but not on β-arrestin pathway.

Short-term exposure to air pollution and biomarkers of cardiovascular effect: A repeated measures study.

To help understand the pathophysiologic mechanisms linking air pollutants and cardiovascular disease (CVD), we employed a repeated measures design to investigate the associations of four short-term air pollution exposures - particulate matter less than 2.5μm in diameter (PM2.5), nitrogen dioxide (NO2), ozone (O3) and sulfur dioxide (SO2), with two blood markers involved in vascular effects of oxidative stress, soluble lectin-like oxidized LDL receptor-1 (sLOX-1) and nitrite, using data from the Multi-Ethnic Study of Atherosclerosis (MESA). Seven hundred and forty participants with plasma sLOX-1 and nitrite measurements at three exams between 2002 and 2007 were included. Daily PM2.5, NO2, O3 and SO2 zero to seven days prior to blood draw were estimated from central monitors in six MESA regions, pre-adjusted using site-specific splines of meteorology and temporal trends, and an indicator for day of the week. Unconstrained distributed lag generalized estimating equations were used to estimate net effects over eight days with adjustment for sociodemographic and behavioral factors. The results showed that higher short-term concentrations of PM2.5, but not other pollutants, were associated with increased sLOX-1 analyzed both as a continuous outcome (percent change per interquartile increase: 16.36%, 95%CI: 0.1-35.26%) and dichotomized at the median (odds ratio per interquartile increase: 1.21, 95%CI: 1.01-1.44). The findings were not meaningfully changed after adjustment for additional covariates or in several sensitivity analyses. Pollutant concentrations were not associated with nitrite levels. This study extends earlier experimental findings of increased sLOX-1 levels following PM inhalation to a much larger population and at ambient concentrations. In light of its known mechanistic role in promoting vascular disease, sLOX-1 may be a suitable translational biomarker linking air pollutant exposures and cardiovascular outcomes.

Rutin attenuates Sorafenib-induced Chemoresistance and Autophagy in Hepatocellular Carcinoma by regulating BANCR/miRNA-590-5P/OLR1 Axis.

Rutin, the main component of Potentilla discolor Bunge, was proven to exhibit anti-tumor properties. Sorafenib (SO) is conventionally used in chemotherapy against hepatocellular carcinoma (HCC), but acquired resistance developed during long-term therapy limits its benefits. This study aimed to explore the molecular mechanism of rutin in SO-induced autophagy and chemoresistance in HCC. Sixty-eight paired HCC patients who received the same chemotherapy treatment were obtained. We also established two SO resistance cell lines and then utilized high-throughput RNA sequencing to explore their long non-coding RNA (lncRNA) expression profiles. The target microRNA (miRNA) and downstream mRNA were also explored. Our results indicated that rutin treatment attenuates autophagy and BANCR expression in SO resistance cells. Transmission electron microscopy clearly showed a significantly decreased number of autophagosomes after rutin-treated HepG2/SO and HCCLM3/SO cells. BANCR knockdown promotes the sensitivity of SO resistance cells to SO. Further study found that BANCR acts as a molecular sponge of miR-590-5P to sequester miR-590-5P away from oxidized low-density lipoprotein receptor 1 (OLR1) in HCC cells. Furthermore, in vivo study demonstrated that rutin could inhibit autophagy through the BANCR/miRNA-590-5P/OLR1 axis. Our findings suggest that rutin could regulate autophagy by regulating BANCR/miRNA-590-5P/OLR1 axis.

Adiponectin forms a complex with atherogenic LDL and inhibits its downstream effects

Adiponectin, an adipocyte-derived protein, has antiatherogenic and antidiabetic effects, but how it confers the atherogenic effects is not well known. To study the antiatherogenic mechanisms of adiponectin, we examined whether it interacts with atherogenic low density lipoprotein (LDL) to attenuate LDL's atherogenicity. L5, the most electronegative subfraction of LDL, induces atherogenic responses similarly to copper-oxidized LDL (oxLDL). Unlike the native LDL endocytosed via the LDL receptor, L5 and oxLDL are internalized by cells via the lectin-like oxidized LDL receptor-1 (LOX-1). Using enzyme-linked immunosorbent assays (ELISAs), we showed that adiponectin preferentially bound oxLDL but not native LDL. In Chinese hamster ovary (CHO) cells transfected with the LOX-1 or LDL receptor, adiponectin selectively inhibited the uptake of oxLDL but not of native LDL, respectively. Furthermore, adiponectin suppressed the internalization of oxLDL in human coronary artery endothelial cells (HCAECs) and THP-1-derived macrophages. Western blot analysis of human plasma showed that adiponectin was abundant in L5 but not in L1, the least electronegative subfraction of LDL. Sandwich ELISAs with anti-adiponectin and anti-apolipoprotein B antibodies confirmed the binding of adiponectin to L5 and oxLDL. In LOX-1-expressing CHO cells, adiponectin inhibited cellular responses to oxLDL and L5, including nuclear factor-κB activation and extracellular signal-regulated kinas phosphorylation. In HCAECs, adiponectin inhibited oxLDL-induced endothelin-1 secretion and extracellular signal-regulated kinase phosphorylation. Conversely, oxLDL suppressed the adiponectin-induced activation of adenosine monophosphate-activated protein kinase in COS-7 cells expressing adiponectin receptor AdipoR1. Our findings suggest that adiponectin binds and inactivates atherogenic LDL, providing novel insight into the antiatherogenic mechanisms of adiponectin.

Pyrogallol-Phloroglucinol-6 6-Bieckol on Attenuates High-Fat Diet-Induced Hypertension by Modulating Endothelial-to-Mesenchymal Transition in the Aorta of Mice.

Endothelial-to-mesenchymal transition (EndMT), which is involved in the development of various cardiovascular diseases, is induced by dyslipidemia or obesity. In dyslipidemia, the increased levels of oxidized low-density lipoproteins (oxLDL) upregulated the lectin-type oxidized LDL receptor 1 (Lox-1), which then upregulated the down signaling pathways of PKC-α/MMPs/TGF-β/SMAD2 or 3 and increased the EndMT. In this study, we investigated the effect of pyrogallol-phloroglucinol-6,6-bieckol (PPB), which is a compound of Ecklonia cava (E. cava), on decreased blood pressure (BP) by attenuating the EndMT in a high-fat diet- (HFD-) fed animal model. We also investigated PPB's attenuation effect on EndMT in oxLDL-treated mouse endothelial cells as an in vitro model. The results indicated that, in the aorta or endothelial cells of mice, the HFD or oxLDL treatment significantly increased the expression of Lox-1/PKC-α/MMP9/TGF-β/SMAD2/SMAD3. The PPB treatment significantly decreased its expression. In contrast, the HFD or oxLDL treatment significantly decreased the expression of the EC markers (PECAM-1 and vWF) while the PPB treatment significantly increased them. Moreover, the HFD or oxLDL treatment significantly increased the expression of the mesenchymal cell markers (α-SMA and vimentin) while PPB treatment significantly decreased them. PPB decreased the intima-media thickness and extracellular matrix amount of the aorta and attenuated the BP, which was increased by the HFD. In conclusion, PPB attenuated the upregulation of Lox-1/PKC-α/MMP9/TGF-β/SMAD2 and 3 and restored the EndMT in HFD-fed animals. Moreover, PPB showed a restoring effect on HFD-induced hypertension.

Accumulation of LOX-1+ PMN-MDSCs in nasopharyngeal carcinoma survivors with chronic hepatitis B might permit immune tolerance to epstein-barr virus and relate to tumor recurrence.

Chronic hepatitis B (CHB) has been reported to be associated with impaired prognosis for patients with nasopharyngeal carcinoma (NPC). However, the latent mechanism is unclear. Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) induce immune suppression in CHB and promote the development of hepatocellular carcinoma. Lectin-type oxidized LDL receptor-1 (LOX-1) was recently identified as a specific marker for PMN-MSDC. We found NPC survivors with CHB had high levels of LOX-1+ PMN-MDSCs. LOX-1+ PMN-MDSCs significantly reduced T cell proliferation and activation. Endoplasmic reticulum stress was induced in LOX-1+ PMN-MDSCs. In addition, LOX-1+ PMN-MDSCs increased their expression of NOX2, a key reactive oxygen species (ROS)-related genes, and levels of ROS illustrated by the DCFDA test. The ROS inhibitor N-acetylcysteine abrogated the suppression of LOX-1+ PMN-MDSCs on T cell activation. The EBV DNA-positivity rate was higher in NPC survivors with CHB than in NPC patients without CHB. Those presenting with positive EBV DNA displayed higher LOX-1+ PMN-MDSC levels. LOX-1+ PMN-MDSCs suppressed the CD8+ T cell response against EBV. This study revealed LOX-1+ PMN-MDSC accumulation and activation in NPC survivors with CHB. LOX-1+ PMN-MDSCs might suppress the host immune response to EBV through ER stress/ROS pathway. These results explained the association of CHB with unfavorable NPC prognosis.

Colchicine inhibits the prothrombotic effects of oxLDL in human endothelial cells

BackgroundTissue Factor (TF) plays a pivotal role in coronary thrombosis. Oxidized low-density lipoproteins (oxLDL) are crucial in development of atherosclerosclerosis. Moreover, oxLDL are known to induce TF expression on several cell types including endothelial cells. The lectin-type oxidized LDL receptor 1 (LOX-1) represent the oxLDL receptor. Colchicine is an anti-mitotic drug recently proven to have beneficial effects in cardiovascular disease via unknown mechanisms. Thus, we aim at investigating colchicine effects on TF expression in oxLDL stimulated human vascular endothelial cells (HUVEC). Some molecular mechanism(s) potentially involved were investigated. MethodsHUVEC were pre-incubated with colchicine 10 μM for 1 h and then stimulated with oxLDL (50 μg/mL). TF gene (RT-PCR), protein (western blot), surface expression (FACS) and procoagulant activity (FXa generation assay) were measured. TF translocation to cell surface was investigated by immunofluorescence. NF-κB/IκB axis was examined by western blot analysis and translocation assay. Finally, LOX-1 expression was also investigated. ResultsColchicine significantly reduced TF gene and protein expression as well as its procoagulant activity in oxLDL-treated HUVEC. These effects seem to be related mainly to action of colchicine on microtubules that, in turn, modulate TF trafficking in the cytoplasm, NF-κB/IκB pathway and LOX-1 expression. ConclusionsData of the present study, although in vitro, indicate that one of the hypothetical mechanisms by which colchicine exert protective cardiovascular effects might be its ability to inhibit the pro-thrombotic activity of oxLDL.

Tanshinone IIA attenuates atherosclerosis via inhibiting NLRP3 inflammasome activation.

Tanshinone IIA (Tan IIA) possesses potent anti-atherogenic function, however, the underlying pharmacological mechanism remains incompletely understood. Previous studies suggest that oxidized LDL (oxLDL)-induced NLRP3 (NOD-like receptor (NLR) family, pyrin domain-containing protein 3) inflammasome activation in macrophages plays a vital role in atherogenesis. Whether the anti-atherogenic effect of Tan IIA relies on the inhibition of the NLRP3 inflammasome has not been investigated before. In this study, we found that Tan IIA treatment of high-fat diet fed ApoE-/- mice significantly attenuated NLRP3 inflammasome activation in vivo. Consistently, Tan IIA also potently inhibited oxLDL-induced NLRP3 inflammasome activation in mouse macrophages. Mechanically, Tan IIA inhibited NF-κB activation to downregulate pro-interleukin (IL) -1β and NLRP3 expression, and decreased oxLDL-induced expression of lectin-like oxidized LDL receptor-1 (LOX-1) and cluster of differentiation 36 (CD36), thereby attenuating oxLDL cellular uptake and subsequent induction of mitochondrial and lysosomal damage — events that promote the NLRP3 inflammasome assembly. Through regulating both the inflammasome ‘priming’ and ‘activation’ steps, Tan IIA potently inhibited oxLDL-induced NLRP3 inflammasome activation, thereby ameliorating atherogenesis.

Role of LOX-1 (Lectin-Like Oxidized Low-Density Lipoprotein Receptor 1) as a Cardiovascular Risk Predictor: Mechanistic Insight and Potential Clinical Use.

Atherosclerosis, the underlying cause of cardiovascular disease (CVD), is a worldwide cause of morbidity and mortality. Reducing ApoB-containing lipoproteins-chiefly, LDL (low-density lipoprotein)-has been the main strategy for reducing CVD risk. Although supported by large randomized clinical trials, the persistence of residual cardiovascular risk after effective LDL reduction has sparked an intense search for other novel CVD biomarkers and therapeutic targets. Recently, Lox-1 (lectin-type oxidized LDL receptor 1), an innate immune scavenger receptor, has emerged as a promising target for early diagnosis and cardiovascular risk prediction and is also being considered as a treatment target. Lox-1 was first described as a 50 kDa transmembrane protein in endothelial cells responsible for oxLDL (oxidized LDL) recognition, triggering downstream pathways that intensify atherosclerosis via endothelial dysfunction, oxLDL uptake, and apoptosis. Lox-1 is also expressed in platelets, where it enhances platelet activation, adhesion to endothelial cells, and ADP-mediated aggregation, thereby favoring thrombus formation. Lox-1 was also identified in cardiomyocytes, where it was implicated in the development of cardiac fibrosis and myocyte apoptosis, the main determinants of cardiac recovery following an ischemic insult. Together, these findings have revealed that Lox-1 is implicated in all the main steps of atherosclerosis and has encouraged the development of immunoassays for measurement of sLox-1 (serum levels of soluble Lox-1) to be used as a potential CVD biomarker. Finally, the recent development of synthetic Lox-1 inhibitors and neutralizing antibodies with promising results in animal models has made Lox-1 a target for drug development. In this review, we discuss the main findings regarding the role of Lox-1 in the development, diagnosis, and therapeutic strategies for CVD prevention and treatment.

Investigating oxidized LDL receptor 1 (OLR1) polymorphisms as putative genetic markers for polycystic ovary syndrome

Polycystic ovary syndrome has a perplexing pathophysiology driven by genetic and environmental stimuli wherein the propensity for gynaecological and cardiometabolic complications is well recognized. Oxidized low density lipoprotein is a vital player in inducing endothelial dysfunction and downstream atherosclerotic processes by binding to its receptor oxidized LDL receptor 1 (OLR1). We have undertaken this case-control study to investigate whether common polymorphisms of OLR1 (K167N and 3’UTR C188T) contribute to risk of PCOS development and its related traits. Genotyping of K167N and 3’UTR C188T polymorphisms of OLR1 by direct sequencing and restriction fragment length polymorphism techniques using RsaI, respectively was carried out in 298 women with PCOS and 147 controls. Genotype and genotype-phenotype analysis was performed using additive model with appropriate statistical tests. There were no significant differences in genotypic frequency distributions between PCOS women and controls. However, K167N polymorphism showed significant association with decreased insulin levels and homeostasis model assessment of insulin resistance and increased quantitative insulin sensitivity check index, thereby ameliorating insulin resistance in women with PCOS. Contrastingly, this variant was significantly associated with increased waist-hip ratio, fasting glucose levels coupled with diminished LH levels and LH:FSH ratio in controls. The C188T polymorphism showed significant association with increased LDL only in women with PCOS. Therefore, although we did not detect significant associations of either polymorphism with PCOS susceptibility, our genotype-phenotype analysis showed that they differentially influenced metabolic traits of insulin resistance and dyslipidemia, and gonadotropin-related parameters in controls and women with PCOS. To the best of our knowledge, ours is the first study to highlight that OLR1 could be an important predisposing genetic factor for PCOS-related traits.

Short-term exposure to air pollution and novel markers of cardiovascular effect: a repeated measures study in the Multi-Ethnic Study of Atherosclerosis (MESA)

Background: Several pathophysiologic mechanisms have been proposed to underlie the associations between ambient air pollutants and cardiovascular disease. We employed a repeated measures design to investigate the short-term associations of outdoor concentrations of four air pollutants – particulate matter smaller than 2.5 micrometers in diameter (PM2.5), nitrogen dioxide (NO2), ozone (O3) and sulfur dioxide (SO2) – with two blood markers involved in vascular effects of oxidative stress, soluble lectin-like oxidized LDL receptor-1 (sLOX-1) and nitrite, using data from the MESA study.Methods: 740 participants who submitted blood samples at three MESA exams between 2002 and 2007 were included. sLOX-1 and nitrite were measured in plasma samples. Daily concentrations of PM2.5, NO2, O3 and SO2 0-7 days prior to blood draw at each exam were estimated from central monitors in the six MESA regions, pre-adjusted using splines of meteorology, indicators for day of the week, and splines of site-specific time trend. Unconstrained distributed lag linear mixed effect models and generalized estimating equations were used to estimate net effects over several days with adjustment for demographic, socioeconomic and behavioral factors.Results: Median detectable nitrite and sLOX-1 concentrations were 24.7 umol/L and 94.5 pg/ml, respectively. Higher short-term PM2.5 concentrations, but not other pollutants, were associated with elevated sLOX-1 level analyzed both as a continuous outcome (percent change per interquartile increase: 18.5%, 95%CI: 2.4-37.2%) and dichotomized at the median (odds ratio per interquartile increase: 1.21, 95%CI: 1.01-1.44); the finding was not meaningfully changed after adjustment for additional covariates or in several sensitivity analyses. Pollutant concentrations were not associated with nitrite levels. Conclusion: This study adds to the evidence that short-term PM2.5 exposure is associated with higher sLOX-1 and supports the mechanistic hypothesis that oxidative modification of endogenous phospholipids in the lung by PM2.5 drives vascular endothelial cell activation via cell surface pattern recognition receptors.

Systemic Amelioration via Curcumin in Rats following Splenectomy: Lipid Profile, Endothelial and Oxidative Damage

Background We investigated the postsurgical effects of splenectomy with additional curcumin therapy, as an antioxidant, anti-inflammatory substance among the lipid profile and histopathological changes. Materials and Methods 32 rats were randomly divided into four groups: control group (L): laparotomy, sham group: splenectomy (S), splenectomy group treated with curcumin (SC) and splenectomy group treated with corn oil (SCO) for 28 days. The primary outcomes; total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), oxidized LDL (ox-LDL) very-low-density lipoprotein (VLDL) and lectin-type oxidized LDL receptor 1 (LOX-1), secondary outcomes: nuclear factor kappa B (NF-кB), malondialdehyde (MDA), glutathione peroxidase (GPx), superoxide dismutase (SOD) were measured. Histopathological changes were examined in vascular, intestinal and lung tissues. The analysis was performed by ANOVA. Results TG, LDL, ox-LDL, and LOX-1 elevated in S group while reduced by curcumin compared with L group (p < 0.05). Serum and tissue levels of NF-кB and MDA were higher in S group and lower in SC group than L group (p < 0.05). Serum and intestinal levels of SOD and GPx increased in L group while reduced by curcumin (p < 0.05). Total histopathological scores of intestinal tissues were higher in S and SCO groups compared to L and SC groups (p < 0.05). No major changes in vascular and lung tissues were observed except the lymphoid follicles which was higher in S and SCO groups compared to L and SC groups (p < 0.05). Conclusions Curcumin partially improved the lipid profile dysfunction by modulating NF-кB, MDA, SOD, and GPx in splenectomized rats while less likely improving any vascular and alveolar regeneration.

LDL receptors, caveolae and cholesterol in endothelial dysfunction: oxLDLs accomplices or victims?

Oxidized LDLs (oxLDLs) and oxysterols play a key role in endothelial dysfunction and the development of atherosclerosis. The loss of vascular endothelium function negatively impacts vasomotion, cell growth, adhesiveness and barrier functions. While for some of these disturbances, a reasonable explanation can be provided from a mechanistic standpoint, for many others, the molecular mediators that are involved are unknown. Caveolae, specific plasma membrane domains, have recently emerged as targets and mediators of oxLDL-induced endothelial dysfunction. Caveolae and their associated protein caveolin-1 (Cav-1) are involved in oxLDLs/LDLs transcytosis, mainly through the scavenger receptor class B type 1 (SR-B1 or SCARB1). In contrast, oxLDLs endocytosis is mediated by the lectin-like oxidized LDL receptor 1 (LOX-1), whose activity depends on an intact caveolae system. In addition, LOX-1 regulates the expression of Cav-1 and vice versa. On the other hand, oxLDLs may affect cholesterol plasma membrane content/distribution thus influencing caveolae architecture, Cav-1 localization and the associated signalling. Overall, the evidence indicate that caveolae have both active and passive roles in oxLDL-induced endothelial cell dysfunction. First, as mediators of lipid uptake and transfer in the subendothelial space and, later, as targets of changes in composition/dynamics of plasma membrane lipids resulting from increased levels of circulating oxLDLs. Gaining a better understanding of how oxLDLs interact with endothelial cells and modulate caveolae-mediated signalling pathways, leading to endothelial dysfunction, is crucial to find new targets for intervention to tackle atherosclerosis and the related clinical entities. LINKED ARTICLES: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

Effect of aerobic and resistance exercise training on inflammation, endothelial function and ambulatory blood pressure in middle-aged hypertensive patients.

The current randomized controlled trial tested the hypothesis that both aerobic training and dynamic resistance training will improve inflammation, endothelial function and 24-h ambulatory blood pressure (ABP) in middle-aged adults with hypertension, but aerobic training would be more effective. Forty-two hypertensive patients on at least one antihypertensive medication (19 men/23 women; 30-59 years of age) were randomly assigned to 12 weeks of supervised aerobic training (n = 15), resistance training (n = 15) or a nonexercise control (n = 12) group. Inflammation, endothelial function, 24-h ABP and related measures were evaluated at pre and postintervention. We found that aerobic training and resistance training were well tolerated. Both aerobic training and resistance training reduced daytime systolic ABP (-7.2 ± 7.9 and -4.4 ± 5.8 mmHg; P < 0.05) and 24-h systolic ABP (-5.6 ± 6.2 and -3.2 ± 6.4 mmHg; P < 0.05). aerobic training and resistance training both improved brachial artery flow-mediated dilation by 1.7 ± 2.8 and 1.4 ± 2.6%, respectively (7.59 ± 3.36 vs. 9.26 ± 2.93 and 7.24 ± 3.18 vs. 8.58 ± 2.37; pre vs. post P < 0.05). However, only aerobic training decreased markers of inflammation (C-reactive protein, monocyte chemoattractant protein-1, vascular cell adhesion molecule-1 and lectin-like oxidized LDL receptor-1) and endothelin-1 and increased nitrite and nitrate levels (P < 0.05). Healthcare providers should continue to emphasize aerobic training for hypertension management given the established role of nitric oxide, endothelin-1 and chronic low-level inflammation in the pathogenesis of cardiovascular disease. However, our study demonstrates that resistance training should also be encouraged for middle-aged hypertensive patients. Our results also suggest that even if patients are on antihypertensive medications, regular aerobic training and resistance training are beneficial for blood pressure control and cardiovascular disease risk reduction.

Serum LOX-1, ADMA and hs-CRP as Biomarkers of Ischemic Heart Disease in Chronic kidney Disease Patients

Abstracts Background: Ischemic heart disease (IHD) is the main cause of death in patients with chronic kidney disease (CKD)with coronary atherosclerosis , which could be predicted by inflammatory biomarkers , as high sensitive C-reactive protein (hs-CRP), IHD is linked to other independent risk factors as asymmetric dimethylarginine (ADMA) and lectin-like oxidized LDL receptor-1(LOX-1),which have proven roles in atherogenesis .objective to evaluate the clinical significance of ADMA and LOX-1 in addition to hs-CRP as biomarkers of IHD in ESRD patients with regular hemodialysis. Subjects and method: Patients groups included 27 patients under hemodialysis with known IHD (Subgroup Ia), 13 patients under hemodialysis without IHD (Subgroup Ib), 19 patients with CKD under conservative treatment (Subgroup Ic). And A control group of 29 healthy volunteers (group II) serum hs-CRP, ADMA, and LOX-1 were assayed. Results: the value of hs-CRP, ADMA and LOX-1 showed statistically significant increase in subgroup Ia versus subgroup Ib, also between subgroup Ib and subgroup Ic. Furthermore there is a highly statistical significant difference between different subgroups and control group. Correlation studies in subgroup Ia between hs-CRP, ADMA and LOX-1 revealed a statistically significant positive correlation. Conclusion: the combined use of hs-CRP and ADMA or LOX-1 showed to be valid for differentiating ESRD with IHD from ESRD without IHD. Serum levels of ADMA and LOX-1 could be relevant and convenient biomarkers for IHD in patients with CKD and its use beside hs-CRP adds more strength and specification to its known predictive value.

A small-molecule inhibitor of lectin-like oxidized LDL receptor-1 acts by stabilizing an inactive receptor tetramer state

The C-type lectin family member lectin-like oxidized LDL receptor-1 (LOX-1) has been object of intensive research. Its modulation may offer a broad spectrum of therapeutic interventions ranging from cardiovascular diseases to cancer. LOX-1 mediates uptake of oxLDL by vascular cells and plays an important role in the initiation of endothelial dysfunction and its progression to atherosclerosis. So far only a few compounds targeting oxLDL-LOX-1 interaction are reported with a limited level of characterization. Here we describe the identification and characterization of BI-0115, a selective small molecule inhibitor of LOX-1 that blocks cellular uptake of oxLDL. Identified by a high throughput screening campaign, biophysical analysis shows that BI-0115 binding triggers receptor inhibition by formation of dimers of the homodimeric ligand binding domain. The structure of LOX-1 bound to BI-0115 shows that inter-ligand interactions at the receptor interfaces are key to the formation of the receptor tetramer thereby blocking oxLDL binding.

Increased APOE glycosylation plays a key role in the atherogenicity of L5 low-density lipoprotein.

Low-density lipoprotein (LDL) is heterogeneous, composed of particles with variable atherogenicity. Electronegative L5 LDL exhibits atherogenic properties in vitro and in vivo, and its levels are elevated in patients with increased cardiovascular risk. Apolipoprotein E (APOE) content is increased in L5, but what role APOE plays in L5 function remains unclear. Here, we characterized the contributions of APOE posttranslational modification to L5's atherogenicity. Using two-dimensional electrophoresis and liquid chromatography-mass spectrometry, we studied APOE's posttranslational modification in L5 from human plasma. APOE structures with various glycan residues were predicted. Molecular docking and molecular dynamics simulation were performed to examine the functional changes of APOE resulting from glycosylation. We also examined the effects of L5 deglycosylation on endothelial cell apoptosis. The glycan sequence N-acetylgalactosamine, galactose, and sialic acid was consistently expressed on serine 94, threonine 194, and threonine 289 of APOE in L5 and was predicted to contribute to L5's negative surface charge and hydrophilicity. The electrostatic force between the negatively charged sialic acid-containing glycan residue of APOE and positively charged amino acids at the receptor-binding area suggested that glycosylation interferes with APOE's attraction to receptors, lipid-binding ability, and lipid transportation and metabolism functions. Importantly, L5 containing glycosylated APOE induced apoptosis in cultured endothelial cells through lectin-like oxidized LDL receptor-1 (LOX-1) signaling, and glycosylation removal from L5 attenuated L5-induced apoptosis. APOE glycosylation may contribute to the atherogenicity of L5 and be a useful biomarker for rapidly quantifying L5.