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1.
Braz J Med Biol Res ; 54(3): e9386, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33470395

RESUMO

Atherosclerosis could be induced by multiple factors, including hypertension, hyperlipidemia, and smoking, and its pathogenesis has not been fully elucidated. MicroRNAs have been shown to possess great anti-atherosclerotic potential, but the precise function of miR-92a-3p in atherosclerosis and its potential molecular mechanism have not been well clarified. Flow cytometry assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazol-3-ium bromide (MTT) assay were performed to evaluate effects of oxidized low-density lipoprotein (ox-LDL) on proliferation and apoptosis of human umbilical vein endothelial cells (HUVECs), respectively. Malondialdehyde and superoxide dismutase levels in cell lysate were assessed with biochemical kits. The expression levels of miR-92a-3p and Sirtuin6 (SIRT6) in HUVECs exposed to ox-LDL were estimated by real-time quantitative polymerase chain reaction (RT-qPCR). In addition, the protein levels of SIRT6, c-Jun N-terminal kinase (JNK), phosphorylation JNK (p-JNK), p38 mitogen activated protein kinase (p38 MAPK), and phosphorylation p38 MAPK (p-p38 MAPK) were measured by western blot assays. The relationship between miR-92a-3p and SIRT6 was confirmed by dual-luciferase reporter assay. Ox-LDL induced apoptosis and oxidative stress in HUVECs in concentration- and time-dependent manners. Conversely, miR-92a-3p silencing inhibited apoptosis and SIRT6 expression in HUVECs. The overexpression of miR-92a-3p enhanced apoptosis and phosphorylation levels of JNK and p38 MAPK as well as inhibited proliferation in ox-LDL-induced HUVECs. In addition, SIRT6 was a target of miR-92a-3p. miR-92a-3p negatively regulated SIRT6 expression in ox-LDL-induced HUVECs to activate MAPK signaling pathway in vitro. In summary, miR-92a-3p promoted HUVECs apoptosis and suppressed proliferation in ox-LDL-induced HUVECs by targeting SIRT6 expression and activating MAPK signaling pathway.


Assuntos
Sistema de Sinalização das MAP Quinases , Apoptose , Células Endoteliais da Veia Umbilical Humana , Humanos , Lipoproteínas LDL/farmacologia , MicroRNAs/genética , Sirtuínas/genética
2.
PLoS One ; 15(12): e0242543, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33326419

RESUMO

Clinical studies using a range of omega-3 supplements have yielded conflicting results on their efficacy to control inflammation. Omega-3 fatty acids are substrate for the formation of potent immune-protective mediators, termed as specialized pro-resolving mediators (SPM). Herein, we investigated whether observed differences in the potencies of distinct omega-3 supplements were linked with their ability to upregulate SPM formation. Using lipid mediator profiling we found that four commercially available supplements conferred a unique SPM signature profile to human macrophages, with the overall increases in SPM concentrations being different between the four supplements. These increases in SPM concentrations were linked with an upregulation of macrophage phagocytosis and a decreased uptake of oxidized low-density lipoproteins. Pharmacological inhibition of two key SPM biosynthetic enzymes 5-Lipoxygenase or 15-Lipoxygenase reversed the macrophage-directed actions of each of the omega-3 supplements. Furthermore, administration of the two supplements that most potently upregulated macrophage SPM formation and reprogrammed their responses in vitro, to APOE-/- mice fed a western diet, increased plasma SPM concentrations and reduced vascular inflammation. Together these findings support the utility of SPM as potential prognostic markers in determining the utility of a given supplement to regulate macrophage responses and inflammation.


Assuntos
Aterosclerose/prevenção & controle , Suplementos Nutricionais , Ácidos Graxos Ômega-3/administração & dosagem , Leucotrienos/biossíntese , Lipoxinas/biossíntese , Macrófagos/efeitos dos fármacos , Prostaglandinas/biossíntese , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Apolipoproteínas E/imunologia , Araquidonato 15-Lipoxigenase/genética , Araquidonato 15-Lipoxigenase/imunologia , Araquidonato 5-Lipoxigenase/genética , Araquidonato 5-Lipoxigenase/imunologia , Aterosclerose/etiologia , Aterosclerose/imunologia , Aterosclerose/metabolismo , Dieta Ocidental/efeitos adversos , Ácidos Graxos Ômega-3/metabolismo , Feminino , Expressão Gênica , Humanos , Leucotrienos/imunologia , Lipoproteínas LDL/antagonistas & inibidores , Lipoproteínas LDL/farmacologia , Lipoxinas/imunologia , Inibidores de Lipoxigenase/farmacologia , Macrófagos/citologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Knockout para ApoE , Fagocitose/efeitos dos fármacos , Cultura Primária de Células , Análise de Componente Principal , Prostaglandinas/imunologia
3.
Life Sci ; 259: 118241, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32791147

RESUMO

AIMS: Compelling evidences demonstrate that informative RNAs play essential role in therapy of atherosclerosis. Here, we attempted to study the role of hsa_circ_0000345 (circRSF1) in endothelial cell damage through competing endogenous RNA pathway. MATERIALS AND METHODS: Expression of circRSF1, miRNA-758-3p (miR-758) and cyclin D2 (CCND2) was detected using RT-qPCR and western blotting, and the cross-talk among them was identified using dual-luciferase reporter assay and RNA immunoprecipitation. The low-density lipoprotein cholesterol (LDL-C) level was measured with enzyme-linked immunosorbent assay. Cell growth was measured by MTS assay, flow cytometry and caspase-3 activity assay kit. Migration and tube formation were determined by scratch migration assay and tube formation assay, respectively. KEY FINDINGS: CircRSF1 and CCND2 were downregulated, whereas miR-758 was upregulated in serum of patients with atherosclerosis and oxidized low-density lipoprotein (ox-LDL)-treated human aortic endothelial cells (HAECs). Moreover, levels of circRSF1, miR-758 and CCND2 were correlated with circulating LDL-C level. Restoring circRSF1 and silencing miR-758 could improve cell viability, tube formation and migration of HAECs under ox-LDL treatment, as well as attenuated apoptotic rate and caspase-3 activity. However, miR-758 upregulation counteracted the promotion of circRSF1 on cell growth, migration and tube formation in ox-LDL-induced HAECs; so did CCND2 deletion on effect of miR-758 silence. Notably, circRSF1 and CCND2 could competitively bound to miR-758, and circRSF1 positively regulated CCND2 expression via miR-758. SIGNIFICANCE: CircRSF1 could protect against ox-LDL-induced endothelial cell injury in vitro via miR-758/CCND2 axis, suggesting circRSF1 as a potential target for the treatment of atherosclerosis.


Assuntos
Aterosclerose/sangue , Ciclina D2/metabolismo , MicroRNAs/sangue , Proteínas Nucleares/genética , RNA Circular/sangue , Transativadores/genética , Adulto , Apoptose/efeitos dos fármacos , Aterosclerose/genética , Aterosclerose/patologia , Estudos de Casos e Controles , Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclina D2/genética , Células Endoteliais/metabolismo , Feminino , Humanos , Lipoproteínas LDL/sangue , Lipoproteínas LDL/metabolismo , Lipoproteínas LDL/farmacologia , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , RNA Circular/genética , Transdução de Sinais/efeitos dos fármacos
4.
Gene ; 755: 144900, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32554046

RESUMO

Atherosclerosis (AS) is a serious threat to the cardiovascular system. Circular RNA circ_0003645 was found to be differentially expressed in the process of AS. Our study tried to unravel the effect and underlying mechanism of circ_0003645 in endothelial cells treated with oxidized low-density lipoprotein (oxLDL). Si-RNAs and over-circ0003645 were transfected into human umbilical vein endothelial cells (HUVECs), and the expression levels of circ_0003645 and NF-κB mRNA were measured. The protein level of NF-κB, lactate dehydrogenase leakage (LDH leakage), cell viability, and apoptosis were detected. Further, the expression of interleukin (IL)-6, tumor necrosis factor (TNF)-α, ICAM-1, and VCAM-1 were measured. Circ_0003645 was found up-regulated in AS patients and in HUVECs treated with oxLDL. The LDH leakage, cell apoptosis, and expression levels of IL-6, TNF-α, ICAM-1, VCAM-1, NF-κB mRNA, NF-κB protein were all inhibited by circ_0003645 silencing, while cell viability was promoted, and the opposite effects were observed by the overexpression of circ_0003645. In conclusion, circ_0003645 silencing alleviated inflammation and apoptosis, while promoted the viability in oxLDL-induced endothelial cells by the NF-κB pathway.


Assuntos
Aterosclerose/genética , Lipoproteínas LDL/farmacologia , NF-kappa B/metabolismo , RNA Circular/genética , Apoptose/fisiologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Estudos de Casos e Controles , Linhagem Celular , Células Endoteliais/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Interferência de RNA/fisiologia , RNA Circular/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo
5.
Metabolism ; 107: 154227, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32275974

RESUMO

OBJECTIVE: L5, a highly electronegative subtype of low-density lipoprotein (LDL), is likely associated with the development of atherosclerosis and cardiovascular diseases. Normal LDL is composed mainly of apolipoprotein (Apo) B, but L5 has additional proteins such as ApoE. We previously demonstrated that L5 induces endothelial cell senescence by increasing mitochondrial reactive oxygen species. In the present study, we examined the effect of L5 on mitochondrial function in cardiomyocytes. METHODS: We used the Seahorse XF24 extracellular flux analyzer to examine the effect of L5 and its components on mitochondrial energy production. The effects of L5 on mitochondrial morphology were examined by immunofluorescence using MitoTracker Green FM and the corresponding probes in H9c2 cardiomyoblasts. Mitochondrial permeability was assessed by using a calcium-induced swelling assay with a voltage-dependent anion-selective channel (VDAC) inhibitor to determine VDAC-dependence both in vitro and in vivo. L5 without ApoE, referred to as △L5, was used to clarify the role of ApoE in L5-induced mitochondrial dysfunction. RESULTS: L5 not only significantly decreased basal (P < 0.05) and maximal respiration (P < 0.01) but also reduced spare respiratory capacity (P < 0.01) in H9c2 cells. Additionally, L5 caused phosphorylation of Drp1 and mitochondrial fission. Recombinant ApoE mimicked the mitochondrial effects of L5, but △L5 did not cause similar effects. After entering cells, ApoE on L5 colocalized with mitochondrial VDAC and caused mitochondria swelling both in vitro and in vivo. This effect was also seen with recombinant ApoE but not △L5. CONCLUSIONS: ApoE may play an important role in electronegative LDL-induced mitochondrial dysfunction through the opening of the mitochondrial permeability transition pore via the interaction of ApoE and VDAC.


Assuntos
Apolipoproteínas E/metabolismo , Lipoproteínas LDL/farmacologia , Doenças Mitocondriais/induzido quimicamente , Doenças Mitocondriais/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Linhagem Celular , Metabolismo Energético/efeitos dos fármacos , Humanos , Técnicas In Vitro , Lipoproteínas LDL/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Membranas Mitocondriais/metabolismo , Dilatação Mitocondrial/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Espécies Reativas de Oxigênio
6.
BMC Cardiovasc Disord ; 20(1): 120, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32138681

RESUMO

BACKGROUND: Atherosclerosis (AS) is the basis of cardiovascular diseases, characterized by chronic inflammatory and lipid metabolism disorders. Although the anti-inflammatory effect of Klotho in AS has been clearly shown, its lipid-lowering effect is unclear. In this study, we examined the effects of recombinant Klotho (Re-KL) protein on lipid accumulation in foam cells. METHODS: THP-1 cells were exposed to 100 nM phorbol myristate acetate for 24 h and then to oxidized low-density lipoprotein (ox-LDL; 80 mg/mL) to induce foam cell formation. Subsequently, the foam cells were incubated with Re-KL and/or DKK1, an inhibitor of the Wnt/ß-catenin pathway. RESULTS: Oil red O staining and cholesterol intake assay revealed that the foam cell model was constructed successfully. Pre-treatment of the foam cells with Re-KL decreased total cholesterol level, up-regulated the expression of ATP binding cassette transporter A1 (ABCA1) and G1 (ABCG1), and down-regulated the expression of acyl coenzyme a-cholesterol acyltransferase 1 (ACAT1) and members of the scavenger family (SR-A1 and CD36). In addition, the expression of Wnt/ß-catenin pathway-related proteins in foam cells was significantly decreased by the stimulus of Re-KL. Interestingly, the effect of Re-KL was similar to that of DKK1 on foam cells. CONCLUSIONS: The Re-KL-induced up-regulation of reverse cholesterol transport capacity promotes cholesterol efflux and reduces lipid accumulation by suppressing the Wnt/ß-catenin pathway in foam cells.


Assuntos
Anticolesterolemiantes/farmacologia , Colesterol/metabolismo , Células Espumosas/efeitos dos fármacos , Glucuronidase/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Transporte Biológico , Células Espumosas/metabolismo , Humanos , Metabolismo dos Lipídeos/genética , Lipoproteínas LDL/farmacologia , Proteínas Recombinantes/farmacologia , Células THP-1
7.
Mol Cell Biochem ; 467(1-2): 15-25, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32072428

RESUMO

An increasing amount of research showed that endothelial cells (ECs) play crucial role in vascular disorders such as atherosclerosis (AS). LncRNA OIP5-AS1 and microRNA-320a (miR-320a) were reported to exert function in ECs. The purpose of this research was to investigate the functional mechanism of OIP5-AS1 and miR-320a in ox-LDL-treated HUVECs. The RNA levels of OIP5-AS1, miR-320a, and Lectin-like oxidized low-density lipoprotein receptor 1 (LOX1) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The protein levels of LOX1 and cell apoptosis-related genes were determined by Western blot assay. In addition, Cell Counting Kit-8 (CCK-8) and flow cytometry analysis were used to assess cell viability and apoptosis, respectively. Lactate dehydrogenase (LDH) activity was measured using LDH release assay. Besides, the interaction between miR-320a and OIP5-AS1 or LOX1 was predicted by starbase and verified by the dual-luciferase reporter assay. OIP5-AS1 expression was increased and miR-320a expression was decreased in oxidative low-density lipoprotein (ox-LDL)-treated HUVECs. OIP5-AS1 knockdown upregulated ox-LDL-treated HUVECs viability and suppressed apoptosis as well as LDH release. Interestingly, OIP5-AS1 elevated LOX1 level through downregulating miR-320a expression. As expected, miR-320a modulated LOX1 expression to mediate ox-LDL-treated HUVECs progression. Furthermore, OIP5-AS1 knockdown modulated cell progression via regulating miR-320a/LOX1 axis in ox-LDL-treated HUVECs. Our results demonstrated that the depletion of OIP5-AS1 enhanced cell viability and repressed apoptosis as well as LDH release in ox-LDL-treated HUVECs, providing potential target for the treatment of AS.


Assuntos
Endotélio Vascular/citologia , Lipoproteínas LDL/farmacologia , MicroRNAs/genética , RNA Longo não Codificante/genética , Receptores Depuradores Classe E/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , L-Lactato Desidrogenase/metabolismo , Receptores Depuradores Classe E/genética
8.
Life Sci ; 248: 117445, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32081664

RESUMO

AIMS: Atherosclerosis (AS) is a common cardiovascular disease with complicated pathogenesis. Long non-coding RNAs (lncRNAs) have been reported to be associated with AS progression. We aimed to explore the role and underlying mechanism of HOXA transcript at the distal tip (HOTTIP) in AS. MATERIALS AND METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the expression of HOTTIP, miR-490-3p and high mobility group B 1 (HMGB1) in AS patients' sera and oxidized low-density lipoprotein (ox-LDL) induced human aortic vascular smooth muscle cells (HA-VSMCs). Cell Counting Kit-8 (CCK-8) assay and transwell assay were conducted to evaluate the proliferation and migration of HA-VSMCs, respectively. Western blot assay was carried out to determine the levels of proliferating cell nuclear antigen (PCNA), matrix metalloprotein 2 (MMP2), MMP9 and HMGB1. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were conducted to verify the targeting association between HOTTIP and miR-490-3p, as well as miR-490-3p and HMGB1. KEY FINDINGS: HOTTIP and HMGB1 were upregulated and miR-490-3p was downregulated in the sera of AS patients and ox-LDL-stimulated HA-VSMCs. HOTTIP knockdown suppressed ox-LDL induced proliferation and migration in HA-VSMCs. MiR-490-3p was identified as a target of HOTTIP and HOTTIP overexpression abolished the inhibition on cell proliferation and migration mediated by miR-490-3p in ox-LDL-induced HA-VSMCs. Moreover, miR-490-3p inhibition promoted cell proliferation and migration by directly targeting HMGB1 in ox-LDL-induced HA-VSMCs. Besides, HOTTIP knockdown repressed the activation of PI3K-AKT signaling pathway. SIGNIFICANCE: HOTTIP knockdown suppressed cell proliferation and migration by regulating miR-490-3p/HMGB1 axis and PI3K-AKT pathway in ox-LDL-induced HA-VSMCs.


Assuntos
Aterosclerose/genética , Proteína HMGB1/genética , MicroRNAs/genética , Miócitos de Músculo Liso/metabolismo , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , RNA Longo não Codificante/genética , Aorta/metabolismo , Aorta/patologia , Aterosclerose/sangue , Aterosclerose/patologia , Estudos de Casos e Controles , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica , Proteína HMGB1/metabolismo , Humanos , Lipoproteínas LDL/farmacologia , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais
9.
Biomed Res Int ; 2020: 4291327, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32090093

RESUMO

Objectives: Atherosclerosis (AS) is a severe disease in which the inside of an artery narrows because of plaque formation, leading to endothelial injury in the patients. Although it has been found that endothelial nitric oxide synthase (eNOS), which produces a low concentration of NO, is necessary for endothelial function and integrity, the regulatory mechanisms of eNOS expression against the pathogenesis and development of AS are unclear. Evidence has indicated that diet supplementation with L-arginine could reduce the size of the endothelial injury lesions in AS patients. In addition, nonencoding microRNAs (miRNAs) were found to be a promising tool that regulates the expression of eNOS in human endothelial cells. Design: The aim of this research was to explore the role of L-arginine in the development of AS and the mechanisms by which miR-221 influences the possible signaling pathways in endothelial cells during AS. Results: The results suggested that L-arginine could prevent oxidized low-density lipoprotein-induced apoptosis in endothelial cells, which is associated with the downregulation of miR-221. Similar results were also observed in rat AS models. Conclusion: This research could provide potential therapies for the treatment of AS.


Assuntos
Arginina/uso terapêutico , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Dieta Hiperlipídica , Regulação para Baixo/genética , MicroRNAs/genética , Animais , Antagomirs/farmacologia , Aorta/patologia , Apoptose/efeitos dos fármacos , Arginina/farmacologia , Regulação para Baixo/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Lipoproteínas LDL/farmacologia , Masculino , MicroRNAs/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos Sprague-Dawley , Túnica Íntima/patologia , Túnica Média/patologia
10.
Life Sci ; 243: 117287, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31926240

RESUMO

Vascular smooth muscle cell (VSMC) accumulation and endothelial cell dysfunction are associated with pathogenesis of atherosclerosis. Long noncoding RNA taurine up-regulated gene 1 (TUG1) has been reported to play an important role in cardiovascular diseases, including atherosclerosis. However, the regulatory mechanism underlying TUG1 in atherosclerosis is far from understood. VSMC and human umbilical vein endothelial cells (HUVEC) stimulated by oxidized low-density lipoprotein (ox-LDL) were used as cellular model of atherosclerosis. Cell proliferation and apoptosis were detected by CCK-8, flow cytometry and Western blot. The expression levels of TUG1, microRNA (miR)-148b and insulin-like growth factor 2 (IGF2) were measured by quantitative real-time polymerase chain reaction or Western blot. The target association among TUG1, miR-148b and IGF2 was determined by luciferase reporter assay and RNA immunoprecipitation. The expression of TUG1 was increased in ox-LDL-treated VSMC and HUVEC. Silence of TUG1 inhibited proliferation and promoted apoptosis in ox-LDL-treated VSMC but induced proliferation promotion and apoptosis inhibition in HUVEC stimulated by ox-LDL. miR-148b was a target of TUG1 and its knockdown reversed the effect of TUG1 silence on proliferation and apoptosis of VSMC and HUVEC challenged by ox-LDL. IGF2 was a target of miR-148b and miR-148b regulated proliferation and apoptosis in ox-LDL-treated VSMC and HUVEC by targeting IGF2. TUG1 promoted IGF2 protein expression by sponging miR-148b. TUG1 knockdown attenuated ox-LDL-induced injury through regulating proliferation and apoptosis of VSMC and HUVEC by miR-148b/IGF2 axis, providing a novel mechanism for pathogenesis of atherosclerosis.


Assuntos
Apoptose/fisiologia , Proliferação de Células/fisiologia , Fator de Crescimento Insulin-Like II/fisiologia , Lipoproteínas LDL/farmacologia , MicroRNAs/fisiologia , RNA Longo não Codificante/fisiologia , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana , Humanos
11.
Life Sci ; 243: 117270, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31923421

RESUMO

AIMS: The purpose of this study is to investigate the effect of PP2A on the progression of AS and the special molecular mechanism. MAIN METHODS: The expression of PP2A in Human umbilical vein endothelial cells (HUVECs) induced by different concentrations of Ox-LDL was measured by RT-PCR and Western blot. The binding activity of PP2A and LOX-1 was determined by CoIP assay. Western blot was used to measure the protein expression of VCAM-1, ICAM-1 and MCP-1. KEY FINDING: The results revealed that the expression of PP2A was decreased with the increase of Ox-LDL concentration in HUVECs. Overexpression of PP2A alleviated Ox-LDL-induced dysfunction and inflammatory response in HUVECs. The results of Co-immunoprecipitation (CoIP) showed that PP2A had direct effect on LOX-1, and PP2A inhibited the expression of LOX-1. In addition, overexpression of LOX-1 reversed the inhibitory effect of PP2A on Ox-LDL-induced dysfunction and inflammatory response in HUVECs. What is more, PP2A inhibited LOX-1/ROS/MAPK axis. SIGNIFICANCE: it suggests that PP2A alleviates Ox-LDL-induced dysfunction and inflammatory response of HUVECs potentially by regulating the LOX-1/ROS/MAPK axis,which suggests that PP2A has anti-inflammatory effect during the formation of as, and the molecular therapy of PP2A provides a theoretical basis.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Lipoproteínas LDL/farmacologia , Lipoxigenase/metabolismo , Sistema de Sinalização das MAP Quinases , Proteína Fosfatase 2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Relação Dose-Resposta a Droga , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/prevenção & controle , Lipoproteínas LDL/administração & dosagem
12.
Artif Cells Nanomed Biotechnol ; 48(1): 107-115, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852304

RESUMO

Atherosclerosis is a potentially life-threatening cardiovascular disease characterized by chronic endothelial inflammation and the formation of atherosclerotic lesions. Circulating ox-LDL is known to induce atherosclerosis by triggering oxidative stress, the expression of inflammatory mediators and adhesion molecules, as well as downregulating the atheroprotective transcriptional factor KLF2. Aloperine is an alkaloid compound isolated from the plant Sophora alopecuroides. Here, we employed various experimental methods to determine the effects of aloperine on ox-LDL-induced markers of atherosclerosis. DHE staining revealed that aloperine may restore the oxidant/antioxidant balance in HUVECs by reducing the level of ROS and rescuing the reduction in NOQ-1 and GCLC induced by ox-LDL. Aloperine treatment reduced ox-LDL-induced expression of IL-6, MCP-1, VCAM-1, and E-selectin and rescued the reduction in KLF2. Aloperine also downregulated ox-LDL-induced expression of the LOX-1. We also demonstrate that aloperine improved cell viability and inhibited the adhesion of U937 monocytes to HUVECs. Finally, we demonstrate that the effects of aloperine are mediated through the rescue of KLF2 expression via suppression of the phosphorylation of p53 protein. Together, our results implicate the potential of aloperine as a safe and effective antiatherosclerosis treatment.


Assuntos
Citoproteção/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/patologia , Lipoproteínas LDL/farmacologia , Piperidinas/farmacologia , Adesão Celular/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Fatores de Transcrição Kruppel-Like/metabolismo , Monócitos/citologia , Monócitos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Piperidinas/uso terapêutico , Receptores Depuradores Classe E/metabolismo
13.
J Biochem Mol Toxicol ; 34(2): e22422, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31729780

RESUMO

M1 macrophages serve one edge as proinflammatory and M2 macrophages serve the other edge as an anti-inflammatory macrophage. It appears that a related "switch" in macrophage morphology may also happen in the course of atherosclerosis, which has not yet been elucidated. An atherogenic diet (AD) was given to rats, and induction of macrophage differentiation and the nuclear localization of nuclear factor-kappa B (NFκB) were investigated by Western blot and immunofluorescence. Chemokines were analyzed using an antibody array with 32 target proteins. M2 macrophage transformation was confirmed in diosgenin-treated aorta by immunofluorescence and was validated in vitro using THP-1 cells. MAC387 (macrophage marker) and NFκBp65 (inflammatory hub) were upregulated in oxidatively-modified low-density lipoprotein (OxyLDL) and AD-induced condition. Macrophage differentiation, which induced the formation of inflammatory mediators, was not significantly suppressed by the inhibition of NFκB using dexamethasone. M1 macrophage polarization was identified in OxyLDL-induced monocytes, which are proinflammatory in nature, whereas M2 macrophage polarization was noticed in diosgenin-treated monocytes, which exhibit anti-inflammatory properties. M1-and M2-specific chemokines were analyzed using chemokine antibody array. Furthermore, the expression of proinflammatory macrophage (M1) was noticed in AD-induced aorta and anti-inflammatory macrophage (M2) was observed in diosgenin-treated aorta. This is the first report where, unifying the mechanism of diosgenin as aan nti-atherosclerotic and the expression of M1 and M2 specific chemokines is shown by downregulating NFκB and not by preventing the differentiation of monocyte into a macrophage, but by allowing macrophage to differentiate into M2, which aids in preventing the atherosclerotic progression.


Assuntos
Aorta/metabolismo , Aterosclerose/metabolismo , Polaridade Celular , Citocinas/metabolismo , Diosgenina/farmacologia , Macrófagos/metabolismo , Extratos Vegetais/farmacologia , Fator de Transcrição RelA/metabolismo , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controle , Antígenos CD36/genética , Antígenos CD36/metabolismo , Diferenciação Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Dexametasona/farmacologia , Dieta Aterogênica/efeitos adversos , Dioscorea/química , Diosgenina/uso terapêutico , Humanos , Lipoproteínas LDL/farmacologia , Masculino , Monócitos/metabolismo , Extratos Vegetais/uso terapêutico , Ratos , Transdução de Sinais/efeitos dos fármacos , Células THP-1 , Fator de Transcrição RelA/antagonistas & inibidores , Fator de Transcrição RelA/genética
14.
Microvasc Res ; 127: 103923, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31494123

RESUMO

Minimally modified low-density lipoprotein (mmLDL) is a risk factor for cardiovascular disease. This study was designed to investigate the effect of a Toll-like receptor 4 monoclonal antibody (TLR4 mAb) on mmLDL-induced endothelium-dependent vasodilation (EDV) impairment in mouse mesenteric arteries and to explore the underlying mechanism. Animals were divided into a normal control group, an mmLDL treatment group, and a TLR4 mAb intervention group. The serum concentrations of IL-1ß and TNF-α were detected using enzyme-linked immunosorbent assays (ELISAs). EDV function was measured using a microvascular tension tracing method. The protein levels and mRNA expression of IL-1ß and TNF-α in vascular tissue were detected using western blot analysis and reverse transcription polymerase chain reaction, respectively. TLR4 mAb improved mmLDL-induced EDV functional impairment in a dose-dependent manner. TLR4 mAb significantly upregulated KCa3.1 and KCa2.3 channel protein levels and downregulated TNF-α and IL-1ß expression. These effects were possibly associated with the competitive antagonism of TLR4 mAb on the TLR4 signaling pathway and the downstream NF-κB p65 and p38 MAPK pathways, which are activated by mmLDL. In conclusion, pretreatment with TLR4 mAb lessens mmLDL-induced EDV dysfunction and inhibits overexpression of inflammatory factors. Regulation of the TLR4 pathway, as well as its downstream NF-κB p65 and p38 MAPK pathways, may be an effective strategy for the prevention and treatment of cardiovascular diseases.


Assuntos
Anticorpos Monoclonais/farmacologia , Endotélio Vascular/efeitos dos fármacos , Lipoproteínas LDL/farmacologia , Artérias Mesentéricas/efeitos dos fármacos , Receptor 4 Toll-Like/antagonistas & inibidores , Vasodilatação/efeitos dos fármacos , Animais , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Feminino , Interleucina-1beta/sangue , Interleucina-1beta/genética , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/genética , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/metabolismo , Masculino , Artérias Mesentéricas/imunologia , Artérias Mesentéricas/metabolismo , Camundongos Endogâmicos ICR , Fosforilação , Transdução de Sinais , Canais de Potássio Ativados por Cálcio de Condutância Baixa/genética , Canais de Potássio Ativados por Cálcio de Condutância Baixa/metabolismo , Receptor 4 Toll-Like/imunologia , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
FEBS J ; 287(4): 695-707, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31386799

RESUMO

While increased levels of high-density lipoprotein (HDL)-cholesterol correlate with protection against cardiovascular disease, recent findings demonstrate that HDL function, rather than HDL-cholesterol levels, may be a better indicator of cardiovascular risk. One mechanism by which HDL function can be compromised is through modification by reactive aldehydes such as acrolein (Acro), 4-hydroxynonenal, and malondialdehyde (MDA). In this study, we tested the hypothesis that modification of HDL with reactive aldehydes would impair HDL's athero-protective functions in macrophages. Compared to native HDL, Acro- and MDA-modified HDL have impaired abilities to promote migration of primary peritoneal macrophages isolated from C57BL6/J mice. Incubation of macrophages with MDA-HDL also led to an increased ability to generate reactive oxygen species. Our studies revealed that the changes in HDL function following aldehyde modification are likely not through activation of canonical nuclear factor-kappa B signaling pathways. Consistent with this finding, treatment of either noncholesterol-loaded macrophages or foam cells with modified forms of HDL does not lead to significant changes in expression levels of inflammatory markers. Importantly, our data also demonstrate that changes in HDL function are dependent on the type of modification present on the HDL particle. Our findings suggest that modification of HDL with reactive aldehydes can impair some, but not all, of HDL's athero-protective functions in macrophages.


Assuntos
Aldeídos/química , Expressão Gênica/efeitos dos fármacos , Lipoproteínas HDL/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Acroleína/química , Animais , Movimento Celular/efeitos dos fármacos , Feminino , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Lipoproteínas HDL/química , Lipoproteínas LDL/farmacologia , Macrófagos Peritoneais/citologia , Macrófagos Peritoneais/metabolismo , Masculino , Malondialdeído/química , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Cultura Primária de Células , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
16.
Chem Biol Interact ; 316: 108916, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31870843

RESUMO

Oxidized low-density lipoprotein (ox-LDL)-induced endothelial inflammation plays an important role in the development of cardiovascular diseases. G protein-coupled receptors (GPCR) are gaining traction as potential treatment targets due to their roles in mediating a wide range of physiological processes. GPR120 is a recently identified omega-3 fatty acid receptor. We hypothesized that agonism of GPR120 might attenuate ox-LDL-induced endothelial dysfunction. In the present study, we tested the effects of two GPR120 agonists-GW9508 and TUG-891-in mitigating endothelial insult induced by ox-LDL in human aortic endothelial cells (HAECs). Real-time PCR, western blot, and ELISA analyses were used in our experiments. Our findings demonstrate that GPR120 is downregulated by exposure to ox-LDL, suggesting a role for GPR120 in mediating ox-LDL insult. Furthermore, we found that agonism of GPR120 could suppress oxidative stress and inflammation by inhibiting the production of reactive oxygen species and the expression of proinflammatory cytokines. Importantly, we show that agonism of GPR120 prevents the attachment of monocytes to endothelial cells by suppressing the expression of VCAM-1 and E-selectin. Finally, we show that agonism of GPR120 exerts a remarkable atheroprotective effect by elevating the expression level of Krüppel-like factor 2 (KLF2). Together, our results demonstrate a potential role for specific agonism of GPR120 in the prevention of endothelial damages induced by ox-LDL.


Assuntos
Adesão Celular/efeitos dos fármacos , Lipoproteínas LDL/farmacologia , Metilaminas/farmacologia , Propionatos/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Selectina E/genética , Selectina E/metabolismo , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/prevenção & controle , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Monócitos/citologia , Monócitos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo
17.
Immunology ; 159(2): 221-230, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31663113

RESUMO

Oxidized low-density lipoprotein (LDL) contributes to cardiovascular disease in part by mediating activation and maturation of monocytes and macrophages. Furthermore, co-localization studies using histochemical approaches have implicated a potential role for oxidized LDL as a mediator of interleukin-15 (IL-15) expression in myeloid cells of atherosclerotic plaque. The latter activity could be an important pro-inflammatory mechanism that mediates myeloid cell/T-cell crosstalk. Here, we examined the responses of primary human monocytes to highly oxidized LDL molecules. Oxidized LDL readily induced secretion of chemokines MCP-1 (CCL2) and GRO-α (CXCL1) but unlike lipopolysaccharide (LPS), has limited capacity to induce a variety of other cytokines including tumor necrosis factor-α, IL-6, IL-1ß and interferon-γ-induced protein-10 and also displayed a poor capacity to induce p-Akt or P-S6 signaling. Failure of oxidized LDL to induce IL-1ß secretion was associated with limited induction of caspase-1 activation. Furthermore, despite finding evidence that oxidized LDL could enhance the expression of IL-15 and IL-15 receptor expression in monocytes, we found no evidence that it could confer IL-15 transpresentation capability to these cells. This observation contrasted with induction of IL-15 transpresentation in lipopolysaccharide-stimulated monocytes. Overall, our data suggest that highly oxidized LDL is a selective inducer of monocyte activation. Sterile inflammatory mediators, particularly those implicated in Toll-like receptor 4 signaling, may play a role in vascular pathology but the activities of these agents are not uniform.


Assuntos
Interleucina-15/metabolismo , Interleucina-1beta/metabolismo , Lipoproteínas LDL/farmacologia , Monócitos/efeitos dos fármacos , Caspase 1/metabolismo , Células Cultivadas , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Inflamassomos/imunologia , Inflamassomos/metabolismo , Interleucina-15/imunologia , Interleucina-1beta/imunologia , Lipopolissacarídeos/farmacologia , Monócitos/imunologia , Monócitos/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Interleucina-15/imunologia , Receptores de Interleucina-15/metabolismo , Proteínas Quinases S6 Ribossômicas/metabolismo , Via Secretória , Transdução de Sinais , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo
18.
J Cardiovasc Pharmacol ; 74(6): 566-573, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31815869

RESUMO

FSTL3 as adipokine takes part in dyslipidemia and inflammatory response, but the association of FSTL3 with atherosclerosis is unclear. This study indicated that FSTL3 showed significantly higher level (control: 7.68 ± 3.10 vs. AS: 9.29 ± 2.37 ng/mL; P < 0.001) in atherosclerosis, and FSTL3 expressed higher in plaque of ApoE knockout mice and located in macrophages. Oxidized low-density lipoproteins induced expression and secretion of FSTL3, meanwhile FSTL3 promoted lipid accumulation in macrophages. The advanced study found that FSTL3 upregulated CD36 and LOX-1 expression in a dose-dependent manner; however, FSTL3 also evoked interleukin 1-ß (IL1-ß), monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor-α, and matrix metalloproteinase-9 (MMP-9) secretion in macrophages. On the contrary, that downregulated FSTL3 attenuated expression of oxidized low-density lipoproteins induced CD36, LOX-1, and inflammatory cytokines expressing. All of these results demonstrated that FSTL3 as a novelty cytokine takes part in the process of atherosclerosis through increasing lipid accumulation and inflammation through regulating CD36 and LOX-1 expression.


Assuntos
Aterosclerose/metabolismo , Proteínas Relacionadas à Folistatina/farmacologia , Mediadores da Inflamação/metabolismo , Inflamação/metabolismo , Lipoproteínas LDL/farmacologia , Macrófagos/efeitos dos fármacos , Placa Aterosclerótica , Idoso , Idoso de 80 Anos ou mais , Animais , Aterosclerose/genética , Aterosclerose/patologia , Antígenos CD36/metabolismo , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Proteínas Relacionadas à Folistatina/genética , Proteínas Relacionadas à Folistatina/metabolismo , Humanos , Inflamação/genética , Inflamação/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Pessoa de Meia-Idade , Estudos Retrospectivos , Receptores Depuradores Classe E/metabolismo , Transdução de Sinais
19.
Int J Mol Sci ; 20(23)2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31816893

RESUMO

OBJECTIVE: To investigate the process by which quercetin suppresses atherosclerosis by upregulating MST1-mediated autophagy in RAW264.7 macrophages. METHODS: An in vitro foam cell model was established by culturing RAW264.7 macrophages with oxidized low-density lipoprotein (ox-LDL). The cells were treated with quercetin alone or in combination with the autophagy inhibitor, 3-methyladenine, and autophagy agonist, rapamycin. Cell viability was detected with a CCK-8 kit. Lipid accumulation was detected by oil red O staining, senescence was detected by SA-ß-gal (senescence-associated ß-galactosidase) staining, reactive oxygen species were detected by ROS assay kit. Autophagosomes and mitochondria were detected by transmission electron microscope (TEM), and expression of MST1, LC3-II/I, Beclin1, Bcl-2, P21, and P16 were detected by immunofluorescence and Western blot. RESULTS: Ox-LDL induced RAW264.7 macrophage-derived foam cell formation, reduced survival, aggravated cell lipid accumulation, and induced a senescence phenotype. This was accompanied by decreased formation of autophagosome; increased expression of P53, P21, and P16; and decreased expression of LC3-II/I and Beclin1. After intervention with quercetin, the cell survival rate was increased, and lipid accumulation and senescence phenotype were reduced. Furthermore, the expression of LC3-II/I and Beclin1 were increased, which was consistent with the ability of quercetin to promote autophagy. Ox-LDL also increased the expression of MST1, and this increase was blocked by quercetin, which provided a potential mechanism by which quercetin may protect foam cells against age-related detrimental effects. CONCLUSION: Quercetin can inhibit the formation of foam cells induced by ox-LDL and delay senescence. The mechanism may be related to the regulation of MST1-mediated autophagy of RAW264.7 cells.


Assuntos
Aterosclerose/patologia , Autofagia/efeitos dos fármacos , Progressão da Doença , Células Espumosas/metabolismo , Células Espumosas/patologia , Fator de Crescimento de Hepatócito/metabolismo , Lipoproteínas LDL/farmacologia , Proteínas Proto-Oncogênicas/metabolismo , Quercetina/farmacologia , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Células Espumosas/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Células RAW 264.7 , Sirolimo/farmacologia , Regulação para Cima/efeitos dos fármacos
20.
Cell Death Dis ; 10(12): 909, 2019 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-31797919

RESUMO

Modification of the novel N6-methyladenine (m6A) DNA implicates this epigenetic mark in human malignant disease, but its role in atherosclerosis (AS) is largely unknown. Here, we found that the leukocyte level of m6A but not 5mC DNA modification was decreased with increasing of carotid plaque size and thickness in 207 AS patients as compared with 142 sex- and age-matched controls. Serum low-density lipoprotein (LDL) and leukocyte m6A levels were associated with the progression of carotid plaque size and thickness. Both LDL level and plaque thickness were also independently and negatively related to m6A level. Reduced m6A level was further confirmed in leukocytes and endothelium in western diet-induced AS mice and in oxidized-LDL (ox-LDL)-treated human endothelium and monocyte cells. Decreased m6A level was closely related to the upregulation of AlkB homolog 1 (ALKBH1), the demethylase of m6A. Silencing of ALKBH1 or hypoxia-inducible factor 1α (HIF1α) could rescue the ox-LDL-increased level of MIAT, a hypoxia-response gene. Mechanically, ox-LDL induced HIF1α for transfer into the nucleus. Nuclear HIF1α bound to the ALKBH1-demethylated MIAT promoter and transcriptionally upregulated its expression. Therefore, elevated ALKBH1 level in endothelium and leukocytes reduced m6A level, which is a novel and sensitive biomarker for AS progression.


Assuntos
Adenina/análogos & derivados , DNA/metabolismo , Progressão da Doença , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia , RNA Longo não Codificante/metabolismo , Adenina/metabolismo , Homólogo AlkB 1 da Histona H2a Dioxigenase/sangue , Animais , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Desmetilação/efeitos dos fármacos , Dieta Ocidental , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Feminino , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Modelos Lineares , Lipoproteínas LDL/sangue , Lipoproteínas LDL/farmacologia , Masculino , Camundongos , Pessoa de Meia-Idade , Análise Multivariada , Placa Aterosclerótica/sangue , Regiões Promotoras Genéticas/genética , Ligação Proteica/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Células THP-1
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