Bezafibrate mitigates oxidized-low density lipoprotein (ox-LDL)-induced the attachment of monocytes to endothelial cells: An implication in atherosclerosis.

BACKGROUND: Oxidized forms of low-density lipoproteins (ox-LDL)-associated endothelial dysfunction and subsequent monocyte adhesion play an important role in the development of atherosclerosis (AS). Bezafibrate (BEZ) is a peroxisome proliferator-activated receptor (pan-PPAR) agonist licensed as a hypolipidemic drug. However, the effects of BEZ on endothelial dysfunction are less reported. OBJECTIVES: In this study, we aim to investigate the protective effects of BEZ on ox-LDL-challenged vascular endothelial cells to evaluate its potential value in treating AS. METHODS: Human aortic endothelial cells (HAECs) and THP-1 cells were used to establish an In Vitro AS model. Cell Counting Kit-8 (CCK-8) assay, Real-time PCR, Western blot analysis, and Enzyme-linked immunosorbent assay (ELISA) were used to test the data. RESULTS: As expected, treatment with BEZ suppressed the expression of vascular endothelial growth factor A (VEGF-A), tissue factor (TF), Interleukin 12 (IL-12), tumor necrosis factor (TNF-α), and monocyte chemoattractant protein-1 (MCP-1). BEZ was also found to inhibit ox-LDL-induced expression of the endothelial adhesion molecules vascular cellular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) in HAECs. Correspondingly, BEZ prevented attachment of THP-1 monocytes to ox-LDL-incubated HAECs. Mechanically, BEZ was found to prevent NF-κB activation by reducing the levels of nuclear NF-κB p65 and inhibiting luciferase activity of NF-κB. CONCLUSION: Our study revealed the pharmacological function of BEZ in protecting endothelial dysfunction against ox-LDL, which may provide valuable insight for the clinical application of BEZ.

SREBP-1-mediated lipogenesis confers resistance to ferroptosis and improves endothelial injury.

Atherosclerosis refers to a disease characterized by the formation of lipid plaque deposits within arterial walls, leading to reduced blood flow or blockage of blood outflow. The process of endothelial injury induced by oxidized low-density lipoprotein (ox-LDL) is considered the initial stage of atherosclerosis. Ferroptosis is a form of iron-dependent, non-apoptotic cell death, and current research suggests its association with coronary artery disease (CAD). In this study, we observed a correlation between reduced expression of SREBP-1 and the occurrence of stable CAD. Additionally, during the process of endothelial injury induced by ox-LDL, we also noted decreased expression of the SREBP-1/SCD1/FADS2 and involvement in the ferroptosis process. Mechanistically, ox-LDL induced endothelial injury by inhibiting the lipid biosynthesis process mediated by the SREBP-1/SCD1/FADS2, thereby inducing lipid peroxidation and ferroptosis. On the contrary, overexpression of SREBP-1 or supplementation with monounsaturated fatty acids counteracted iron accumulation, mitochondrial damage, and lipid peroxidation-induced ferroptosis, thereby improving endothelial injury. Our study indicated that the decreased expression of peripheral blood SREBP-1 mRNA is an independent risk factor for stable CAD. Furthermore, in endothelial cells, the lipid biosynthesis process mediated by SREBP-1 could ameliorate endothelial injury by resisting ferroptosis. The study has been registered with the Chinese Clinical Trial Registry, which serves as a primary registry in the World Health Organization International Clinical Trials Registry Platform (ChiCTR2300074315, August 3rd, 2023).

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.

Corilagin relieves atherosclerosis via the toll-like receptor 4 signaling pathway in vascular smooth muscle cells.

INTRODUCTION: Corilagin possesses a diverse range of pharmacologic bioactivities. However, the specific protective effects and mechanisms of action of corilagin in the context of atherosclerosis remain unclear. In this study, we investigated the impact of corilagin on the toll-like receptor (TLR)4 signaling pathway in a mouse vascular smooth muscle cell line (MOVAS) stimulated by oxidized low-density lipoprotein (ox-LDL). Additionally, we examined the effects of corilagin in Sprague-Dawley rats experiencing atherosclerosis. METHODS: The cytotoxicity of corilagin was assessed using the CCK8 assay. MOVAS cells, pre-incubated with ox-LDL, underwent treatment with varying concentrations of corilagin. TLR4 expression was modulated by either downregulation through small interfering (si)RNA or upregulation via lentivirus transfection. Molecular expression within the TLR4 signaling pathway was analyzed using real-time polymerase chain reaction (PCR) and Western blotting. The proliferation capacity of MOVAS cells was determined through cell counting. In a rat model, atherosclerosis was induced in femoral arteries using an improved guidewire injury method, and TLR4 expression in plaque areas was assessed using immunofluorescence. Pathological changes were examined through hematoxylin and eosin staining, as well as Oil-Red-O staining. RESULTS: Corilagin demonstrated inhibitory effects on the TLR4 signaling pathway in MOVAS cells pre-stimulated with ox-LDL, consequently impeding the proliferative impact of ox-LDL. The modulation of TLR4 expression, either through downregulation or upregulation, similarly influenced the expression of downstream molecules. In an in vivo context, corilagin exhibited the ability to suppress TLR4 and MyD88 expression in the plaque lesion areas of rat femoral arteries, thereby alleviating the formation of atherosclerotic plaques. CONCLUSION: Corilagin can inhibit the TLR4 signaling pathway in VSMCs, possibly by downregulating TLR4 expression and, consequently, relieving atherosclerosis.

Lycopene inhibits pyroptosis of endothelial progenitor cells induced by ox-LDL through the AMPK/mTOR/NLRP3 pathway.

The malfunction of endothelial progenitor cells (EPCs) due to ox-LDL is a risk contributor for arteriosclerotic disease. Meanwhile, lycopene possesses anti-inflammatory and antioxidative qualities. This investigation aimed to determine if lycopene can protect EPCs from ox-LDL-induced damage and to elucidate the underlying mechanism. The effects of lycopene on the survival, migration, and tube-forming capacity of EPCs were determined via in vitro assays. Expression of proteins related to pyroptosis and cellular proteins related to AMPK/mTOR/NLRP3 signaling was determined by western blot/flow cytometry. Our results demonstrated that lycopene treatment significantly enhanced proliferation, tube formation, and migration of EPCs stimulated by ox-LDL. Additionally, lycopene was found to suppress pyroptosis in ox-LDL-induced EPCs through the activation of AMPK, which led to the inhibition of mTOR phosphorylation and subsequent downregulation of the downstream NLRP3 inflammasome. In summary, our study suggests that lycopene mitigates ox-LDL-induced dysfunction in EPCs and inhibits pyroptosis via AMPK/mTOR/NLRP3 signaling. Our study suggests that lycopene may act as promising therapies for preventing atherosclerosis.

LY86 facilitates ox-LDL-induced lipid accumulation in macrophages by upregulating SREBP2/HMGCR expression.

LY86, also known as MD1, has been implicated in various pathophysiological processes including inflammation, obesity, insulin resistance, and immunoregulation. However, the role of LY86 in cholesterol metabolism remains incompletely understood. Several studies have reported significant up-regulation of LY86 mRNA in atherosclerosis; nevertheless, the regulatory mechanism by which LY86 is involved in this disease remains unclear. In this study, we aimed to investigate whether LY86 affects ox-LDL-induced lipid accumulation in macrophages. Firstly, we confirmed that LY86 is indeed involved in the process of atherosclerosis and found high expression levels of LY86 in human atherosclerotic plaque tissue. Furthermore, our findings suggest that LY86 may mediate intracellular lipid accumulation induced by ox-LDL through the SREBP2/HMGCR pathway. This mechanism could be associated with increased cholesterol synthesis resulting from enhanced endoplasmic reticulum stress response.

Circ_0002331 Interacts with ELAVL1 to Improve ox-LDL-Induced Vascular Endothelial Cell Dysfunction via Regulating CCND2 mRNA Stability.

Circular RNAs (circRNAs) have been discovered to serve as vital regulators in atherosclerosis (AS). However, the role and mechanism of circ_0002331 in AS process are still unclear. Human umbilical vein endothelial cells (HUVECs) were treated with ox-LDL to establish an in vitro model for AS. The expression levels of circ_0002331, Cyclin D2 (CCND2) and ELAVL1 were analyzed by quantitative real-time PCR. Cell proliferation, apoptosis, migration, invasion and angiogenesis were assessed by EdU assay, flow cytometry, transwell assay and tube formation assay. The protein levels of CCND2, ELAVL1, and autophagy-related markers were detected using western blot analysis. IL-8 level was analyzed by ELISA. The relationship between ELAVL1 and circ_0002331 or CCND2 was analyzed by RIP assay and RNA pull-down assay. Moreover, FISH assay was used to analyze the co-localization of ELAVL1 and CCND2 in HUVECs. Our data showed that circ_0002331 was obviously downregulated in AS patients and ox-LDL-induced HUVECs. Overexpression of circ_0002331 could promote proliferation, migration, invasion and angiogenesis, while inhibit apoptosis, autophagy and inflammation in ox-LDL-induced HUVECs. Furthermore, CCND2 was positively regulated by circ_0002331, and circ_0002331 could bind with ELAVL1 to promote CCND2 mRNA stability. Besides, CCND2 overexpression suppressed ox-LDL-induced HUVECs dysfunction, and its knockdown also reversed the regulation of circ_0002331 on ox-LDL-induced HUVECs dysfunction. In conclusion, circ_0002331 might be a potential target for AS treatment, which could improve ox-LDL-induced dysfunction of HUVECs via regulating CCND2 by binding with ELAVL1.

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.

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.

CircZNF609 sponges miR-135b to up-regulate SEMA3A expression to alleviate ox-LDL-induced atherosclerosis.

The initiation and progression of atherosclerotic plaque caused by abnormal lipid metabolism is one of the main causes of atherosclerosis (AS). Lipid droplet accumulation has become a novel research pointcut for AS treatment in recent years. In AS patients, miR-135b level was up-regulated relative to the normal cases, which showed negative correlations with the levels of Semaphorin 3A (SEMA3A) and circZNF609, separately. The U937-derived macrophages were cultured with ox-LDL to establish AS models in vitro. After that, the lipid accumulation, inflammation, mitochondrial dysfunction and cell death were evaluated by ORO, ELISA, RT-qPCR, western blot, JC-1 and FCM assays respectively. Transfection of the circZNF609 expression vector notably declined lipid accumulation, attenuated inflammation, reduced mitochondrial dysfunction and inhibited cell death in ox-LDL-stimulated cells. The direct binding of miR-135b to circZNF609 in vitro was confirmed using RIP assay, and SEMA3A expression was up-regulated by circZNF609 overexpression. After manipulating the endogenous expressions of circZNF609, miR-135b and SEMA3A, the above damages in ox-LDL-stimulated cells were rescued by inhibition of miR-135b expression and overexpression of circZNF609 or SEMA3A. Besides, the AS mice model was built to demonstrate the excessive lipid accumulation, increasing inflammation and cell death in AS pathogenesis according to the results of HE staining, ELISA and IHC assays, while these damages were reversed after overexpression of circZNF609 or SEMA3A. In AS models, overexpressed circZNF609 prevents the AS progression through depleting miR-135b expression and subsequent up-regulation of SEMA3A expression to overwhelm lipid accumulation, mitochondrial dysfunction and cell death.

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.

Procyanidin B2 alleviates oxidized low-density lipoprotein-induced cell injury, inflammation, monocyte chemotaxis, and oxidative stress by inhibiting the nuclear factor kappa-B pathway in human umbilical vein endothelial cells.

BACKGROUND: Oxidized low-density lipoprotein (ox-LDL) can initiate and affect almost all atherosclerotic events including endothelial dysfunction. In this text, the role and underlying molecular basis of procyanidin B2 (PCB2) with potential anti-oxidant and anti-inflammatory activities in ox-LDL-induced HUVEC injury were examined. METHODS: HUVECs were treated with ox-LDL in the presence or absence of PCB2. Cell viability and apoptotic rate were examined by CCK-8 assay and flow cytometry, respectively. The mRNA and protein levels of genes were tested by RT-qPCR and western blot assays, respectively. Potential downstream targets and pathways of apple procyanidin oligomers were examined by bioinformatics analysis for the GSE9647 dataset. The effect of PCB2 on THP-1 cell migration was examined by recruitment assay. The effect of PCB2 on oxidative stress was assessed by reactive oxygen species (ROS) level, malondialdehyde (MDA) content, and mitochondrial membrane potential (MMP). RESULTS: ox-LDL reduced cell viability, induced cell apoptosis, and facilitated the expression of oxidized low-density lipoprotein receptor 1 (LOX-1), C-C motif chemokine ligand 2 (MCP-1), vascular cell adhesion protein 1 (VCAM-1) in HUVECs. PCB2 alleviated ox-LDL-induced cell injury in HUVECs. Apple procyanidin oligomers triggered the differential expression of 592 genes in HUVECs (|log2fold-change| > 0.58 and adjusted p-value < 0.05). These dysregulated genes might be implicated in apoptosis, endothelial cell proliferation, inflammation, and monocyte chemotaxis. PCB2 inhibited C-X-C motif chemokine ligand 1/8 (CXCL1/8) expression and THP-1 cell recruitment in ox-LDL-stimulated HUVECs. PCB2 inhibited ox-LDL-induced oxidative stress and nuclear factor kappa-B (NF-κB) activation in HUVECs. CONCLUSION: PCB2 weakened ox-LDL-induced cell injury, inflammation, monocyte recruitment, and oxidative stress by inhibiting the NF-κB pathway in HUVECs.

MiR-497-5p regulates ox-LDL-induced dysfunction in vascular endothelial cells by targeting VEGFA/p38/MAPK pathway in atherosclerosis.

Background: The impairment of endothelial cells triggered by oxidized low-density lipoprotein (ox-LDL) stands as a critical event in the advancement of atherosclerosis (AS). MiR-497-5p has been recognized as a potential predictor for AS, but its precise involvement in ox-LDL-induced endothelial cell dysfunction remains to be elucidated. Methods: An in vitro AS cell model was established by exposing human umbilical vein endothelial cells (HUVECs) to 100 µg/mL ox-LDL for 24 h. The assessment of endothelial cell function included evaluating cell viability, caspase-3 activity, inflammatory factors, and oxidative markers. Molecular mechanisms were elucidated through quantitative real-time PCR, Western blot analysis, and luciferase reporter assays. Results: Our investigation revealed that exposure to ox-LDL led to an upregulation in miR-497-5p and p-p38 levels, while downregulating the expression of vascular endothelial growth factor A (VEGFA) and phosphorylated (p)-endothelial nitric oxide synthase (p-eNOS) in HUVECs. Ox-LDL exposure resulted in decreased cell viability and angiogenic capacity, coupled with increased apoptosis, inflammation, and oxidative stress in HUVECs, partially mediated by the upregulation of miR-497-5p. We confirmed VEGFA as a direct target of miR-497-5p. Interfering with VEGFA expression significantly reversed the effects mediated by miR-497-5p silencing in HUVECs exposed to ox-LDL. Conclusions: In summary, our findings demonstrate that miR-497-5p exacerbates ox-LDL-induced dysfunction in HUVECs through the activation of the p38/MAPK pathway, mediated by the targeting of VEGFA.

Oxidized-LDL Induces Metabolic Dysfunction in Retinal Pigment Epithelial Cells.

Recently, mitochondrial dysfunction has gained attention as a causative factor in the pathogenesis and progression of age-related macular degeneration (AMD). Mitochondrial damage plays a key role in metabolism and disrupts the balance of intracellular metabolic pathways, such as oxidative phosphorylation (OXPHOS) and glycolysis. In this study, we focused on oxidized low-density lipoprotein (ox-LDL), a major constituent of drusen that accumulates in the retina of patients with AMD, and investigated whether it could be a causative factor for metabolic alterations in retinal pigment epithelial (RPE) cells. We found that prolonged exposure to ox-LDL induced changes in fatty acid ß-oxidation (FAO), OXPHOS, and glycolytic activity and increased the mitochondrial reactive oxygen species production in RPE cells. Notably, the effects on metabolic alterations varied with the concentration and duration of ox-LDL treatment. In addition, we addressed the limitations of using ARPE-19 cells for retinal disease research by highlighting their lower barrier function and FAO activity compared to those of induced pluripotent stem cell-derived RPE cells. Our findings can aid in the elucidation of mechanisms underlying the metabolic alterations in AMD.

Huayu Qutan Recipe promotes lipophagy and cholesterol efflux through the mTORC1/TFEB/ABCA1-SCARB1 signal axis.

This study aims to investigate the mechanism of the anti-atherosclerosis effect of Huayu Qutan Recipe (HYQT) on the inhibition of foam cell formation. In vivo, the mice were randomly divided into three groups: CTRL group, MOD group and HYQT group. The HYQT group received HYQT oral administration twice a day (20.54 g/kg/d), and the plaque formation in ApoE-/- mice was observed using haematoxylin-eosin (HE) staining and oil red O (ORO) staining. The co-localization of aortic macrophages and lipid droplets (LDs) was examined using fluorescent labelling of CD11b and BODIPY fluorescence probe. In vitro, RAW 264.7 cells were exposed to 50 µg/mL ox-LDL for 48 h and then treated with HYQT for 24 h. The accumulation of LDs was evaluated using ORO and BODIPY. Cell viability was assessed using the CCK-8 assay. The co-localization of LC3b and BODIPY was detected via immunofluorescence and fluorescence probe. LysoTracker Red and BODIPY 493/503 were used as markers for lysosomes and LDs, respectively. Autophagosome formation were observed via transmission electron microscopy. The levels of LC3A/B II/LC3A/B I, p-mTOR/mTOR, p-4EBP1/4EBP1, p-P70S6K/P70S6K and TFEB protein level were examined via western blotting, while SQSTM1/p62, Beclin1, ABCA1, ABCG1 and SCARB1 were examined via qRT-PCR and western blotting. The nuclear translocation of TFEB was detected using immunofluorescence. The components of HYQT medicated serum were determined using Q-Orbitrap high-resolution MS analysis. Molecular docking was employed to identify the components of HYQT medicated serum responsible for the mTOR signalling pathway. The mechanism of taurine was illustrated. HYQT has a remarkable effect on atherosclerotic plaque formation and blood lipid level in ApoE-/- mice. HYQT decreased the co-localization of CD11b and BODIPY. HYQT (10% medicated serum) reduced the LDs accumulation in RAW 264.7 cells. HYQT and RAPA (rapamycin, a mTOR inhibitor) could promote cholesterol efflux, while chloroquine (CQ, an autophagy inhibitor) weakened the effect of HYQT. Moreover, MHY1485 (a mTOR agonist) also mitigated the effects of HYQT by reduced cholesterol efflux. qRT-PCR and WB results suggested that HYQT improved the expression of the proteins ABCA1, ABCG1 and SCARB1.HYQT regulates ABCA1 and SCARB1 protein depending on the mTORC1/TFEB signalling pathway. However, the activation of ABCG1 does not depend on this pathway. Q-Orbitrap high-resolution MS analysis results demonstrated that seven core compounds have good binding ability to the mTOR protein. Taurine may play an important role in the mechanism regulation. HYQT may reduce cardiovascular risk by promoting cholesterol efflux and degrading macrophage-derived foam cell formation. It has been observed that HYQT and ox-LDL regulate lipophagy through the mTOR/TFEB signalling pathway, rather than the mTOR/4EBP1/P70S6K pathway. Additionally, HYQT is found to regulate cholesterol efflux through the mTORC1/TFEB/ABCA1-SCARB1 signal axis, while taurine plays a significant role in lipophagy.

Dendrobine regulates STAT3 to attenuate mitochondrial dysfunction and senescence in vascular endothelial cells triggered by oxidized low-density lipoprotein.

Our previous studies have highlighted the potential therapeutic efficacy of dendrobine, an alkaloid, in atherosclerosis (AS), nevertheless, the underlying mechanism remains unclear. This study employs a combination of network pharmacology and in vitro experiments to explore the regulatory pathways involved. Through network pharmacology, the biological function for intersection targets between dendrobine and AS were identified. Molecular docking was conducted to investigate the interaction between the dominant target and dendrobine. Human umbilical vein endothelial cells (HUVECs) were treated with oxidized low-density lipoprotein (ox-LDL) to mimic AS, and the effects of dendrobine on cell viability, lipid deposition, mitochondrial function, and cellular senescence were evaluated. Subsequently, cells were treated with the mitophagy inhibitor Mdivi-1 and the STAT3 agonist colivelin to assess the role of mitophagy and STAT3 signaling in dendrobine regulation. Intersection targets were associated with biological processes, including reactive oxygen species production. Dendrobine attenuated the effects of ox-LDL treatment on HUVECs, mitigating changes in cell activity, lipid deposition, mitochondrial function, and cellular senescence. Both Mdivi-1 and colivelin treatments resulted in decreased cell viability and increased cellular senescence, with colivelin suppressing mitophagy. Cotreatment with Mdivi-1 and colivelin further aggravated cellular senescence and inhibited FoxO signaling. Together, this study indicated that dendrobine regulated the STAT3/FoxO signaling pathway, alleviating mitochondrial dysfunction and cellular senescence. This study contributes valuable insights to the potential clinical application of dendrobine.

Eugenol Inhibits Ox-LDL-Induced Proliferation and Migration of Human Vascular Smooth Muscle Cells by Inhibiting the Ang II/MFG-E8/MCP-1 Signaling Cascade.

Objective: In this study, we investigated the effect and mechanism of action of eugenol on oxidized low-density lipoprotein (ox-LDL)-induced abnormal proliferation and migration of human vascular smooth muscle cells (HVSMCs). Methods: HVSMCs were treated with 100 ug/mL ox-LDL for 24 hours to establish a cell model. After 1-hour pretreatment, eugenol at concentrations of 5, 25, and 50 uM was added. Cell viability was assessed using an MTT assay, PCNA expression was detected using Western blot, cell cycle distribution was analyzed using flow cytometry, and cell migration ability was evaluated using wound healing and Transwell migration assays. To investigate the mechanisms, Ang II receptors were inhibited by 1000 nM valsartan, MFG-E8 was knocked down by shRNA, MCP-1 was inhibited by siRNA, and MFG-E8 was overexpressed using plasmids. Results: The findings from this study elucidated the stimulatory impact of ox-LDL on the proliferation and functionality of HVSMCs. Different concentrations of eugenol effectively mitigated the enhanced activity of HVSMCs induced by ox-LDL, with 50 uM eugenol exhibiting the most pronounced inhibitory effect. Flow cytometry and Western blot results showed ox-LDL reduced G1 phase cells and increased PCNA expression, while 50 uM eugenol inhibited ox-LDL-induced HVSMC proliferation. In wound healing and Transwell migration experiments, the ox-LDL group showed larger cell scratch filling and migration than the control group, both of which were inhibited by 50 uM eugenol. Inhibiting the Ang II/MFG-E8/MCP-1 signaling cascade mimicked eugenol's effects, while MFG-E8 overexpression reversed eugenol's inhibitory effect. Conclusion: Eugenol can inhibit the proliferation and migration of ox-LDL-induced HVSMCs by inhibiting Ang II/MFG-E8/MCP-1 signaling cascade, making it a potential therapeutic drug for atherosclerosis.

The multi-protective effect of IL-37-Smad3 against ox-LDL induced dysfunction of endothelial cells.

Atherosclerosis is a lipid-driven inflammatory arterial disease, with one crucial factor is oxidized low-density lipoprotein (ox-LDL), which can induce endothelial dysfunction through endoplasmic reticulum stress (ERS). Interleukin-37 (IL-37) exerts vascular protective functions. This study aims to investigates whether IL-37 can alleviate ERS and autophagy induced by ox-LDL, therely potentialy treating atherosclerosis. We found that ox-LDL enhances the wound healing rate in Rat Coronary Artery Endothelial Cells (RCAECs) and IL-37 reduce the ox-LDL-induced pro-osteogenic response, ERS, and autophagy by binding to Smad3. In RCAECs treated with ox-LDL and recombinant human IL-37, the wound healing rate was mitigated. The expression of osteogenic transcription factors and proteins involved in the ERS pathway was reduced in the group pretreated with IL-37 and ox-LDL. However, these responses were not alleviated when Smads silenced. Electron microscopy revealed that the IL-37/Smad3 complex could suppress endoplasmic reticulum autophagy under ox-LDL stimulation. Thus, IL-37 might treat atherosclerosis through its multi-protective effect by binding Smad3.

lncRNA GAPLINC regulates vascular endothelial cell apoptosis in atherosclerosis.

Introduction: In this study, we investigated the role of the long non-coding RNA GAPLINC in atherosclerosis under oxidized low-density lipoprotein (ox-LDL) treatment. Material and methods: We utilized ox-LDL exposed human aortic endothelial cells as an in-vitro model. The expression level of GAPLINC was quantified by qPCR in different times and concentrations of ox-LDL treatment conditions. Cell apoptosis rate and cell cycle profiles were assessed by flow cytometry and TUNEL assay. The target association was confirmed using a luciferase reporter assay and Western blot. Results: We found that GAPLINC expression was induced by ox-LDL treatment, but cell proliferation ability was significantly inhibited. We further confirmed that overexpressing of lncRNA GAPLINC in ox-LDL-exposed HAECs decreased cell proliferation by increasing cell apoptosis and arresting cell cycle in G2/M and S phase. Importantly, the detailed mechanistic analysis elucidated that LncRNA GAPLINC acts as a decoy to sequester miR-183-5p to prevent it from binding to target PDCD4. MiR-183-5p targets GAPLINC, and PDCD4 is a downstream target of miR-183-5p, and the cellular effects of this direct interaction were confirmed by a rescue assay experiment. Conclusions: The present study demonstrates that upregulation of lncRNA GAPLINC represses the binding of miR-183-5p to the PDCD4 promoter region and then promotes PDCD4 expression, thereby inducing cell apoptosis and suppressing endothelial cell proliferation.

Pyroptosis-related non-coding RNAs emerging players in atherosclerosis pathology.

Globally, atherosclerosis a persistent inflammatory condition of the artery walls continues to be the primary cause of cardiovascular illness and death. The ncRNAs are important regulators of important signalling pathways that affect pyroptosis and the inflammatory environment in atherosclerotic plaques. Comprehending the complex interaction between pyroptosis and non-coding RNAs (ncRNAs) offers fresh perspectives on putative therapeutic targets for ameliorating cardiovascular problems linked to atherosclerosis. The discovery of particular non-coding RNA signatures linked to the advancement of atherosclerosis could lead to the creation of novel biomarkers for risk assessment and customised treatment approaches. A thorough investigation of the regulatory networks regulated by these non-coding RNAs has been made possible by the combination of cutting-edge molecular methods and bioinformatics tools. Studying pyroptosis-related ncRNAs in detail appears to be a promising way to advance our understanding of disease pathophysiology and develop focused therapeutic methods as we work to unravel the complex molecular tapestry of atherosclerosis. This review explores the emerging significance of non-coding RNAs (ncRNAs) in the regulation of pyroptosis and their consequential impact on atherosclerosis pathology.