Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 533
Filtrar
1.
Biomed Res Int ; 2021: 9983725, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34471643

RESUMO

Excessive free fatty acid- (FFA-) induced endothelial lipotoxicity is involved in the pathogenesis of atherosclerosis. Endoplasmic reticulum (ER) stress is mechanistically related to endothelial lipotoxicity. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the major oxidatively modified low-density lipoprotein (OxLDL) receptor in endothelial cells and is highly abundant in atherosclerotic lesions. Curcumin reduces the LOX-1 expression; however, the mechanism underlying this effect remains unknown. In the current study, we explored whether curcumin ameliorates palmitic acid- (PA-) induced endothelial lipotoxicity and LOX-1 upregulation by reducing ER stress in human umbilical vein endothelial cells (HUVECs). We built endothelial lipotoxicity in vitro and found that LOX-1 was upregulated after PA stimulation, during which ER stress played an important role. Next, we observed that curcumin substantially alleviated PA-induced lipotoxicity by restoring cell viability, increasing angiogenesis, and decreasing lipid deposition. Furthermore, LOX-1 upregulation in HUVECs was blocked by curcumin, possibly via ER stress suppression. Overall, our findings demonstrated that curcumin alleviates endothelial lipotoxicity and LOX-1 upregulation, and ER stress inhibition may play a critical role in this effect.


Assuntos
Aterosclerose/tratamento farmacológico , Curcumina/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Ácido Palmítico/toxicidade , Receptores Depuradores Classe E/metabolismo , Anti-Inflamatórios não Esteroides/farmacologia , Aterosclerose/induzido quimicamente , Aterosclerose/metabolismo , Aterosclerose/patologia , Sobrevivência Celular , Células Cultivadas , Inibidores Enzimáticos/toxicidade , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos
2.
Sci Rep ; 11(1): 15675, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34344944

RESUMO

Although coagulation abnormalities, including microvascular thrombosis, are thought to contribute to tissue injury and single- or multiple-organ dysfunction in severe influenza, the detailed mechanisms have yet been clarified. This study evaluated influenza-associated abnormal blood coagulation utilizing a severe influenza mouse model. After infecting C57BL/6 male mice with intranasal applications of 500 plaque-forming units of influenza virus A/Puerto Rico/8/34 (H1N1; PR8), an elevated serum level of prothrombin fragment 1 + 2, an indicator for activated thrombin generation, was observed. Also, an increased gene expression of oxidized low-density lipoprotein (LDL) receptor-1 (Olr1), a key molecule in endothelial dysfunction in the progression of atherosclerosis, was detected in the aorta of infected mice. Body weight decrease, serum levels of cytokines and chemokines, viral load, and inflammation in the lungs of infected animals were similar between wild-type and Olr1 knockout (KO) mice. In contrast, the elevation of prothrombin fragment 1 + 2 levels in the sera and intravascular thrombosis in the lungs by PR8 virus infection were not induced in KO mice. Collectively, the results indicated that OLR1 is a critical host factor in intravascular thrombosis as a pathogeny of severe influenza. Thus, OLR1 is a promising novel therapeutic target for thrombosis during severe influenza.


Assuntos
Biomarcadores , Suscetibilidade a Doenças , Infecções por Orthomyxoviridae/complicações , Receptores Depuradores Classe E/metabolismo , Trombose/etiologia , Trombose/metabolismo , Animais , Coagulação Sanguínea , Citocinas/sangue , Modelos Animais de Doenças , Camundongos , Camundongos Knockout , Infecções por Orthomyxoviridae/diagnóstico , Infecções por Orthomyxoviridae/virologia , Tempo de Tromboplastina Parcial , Receptores Depuradores Classe E/genética , Índice de Gravidade de Doença , Trombina/biossíntese , Trombose/diagnóstico , Carga Viral
3.
J Am Heart Assoc ; 10(15): e021707, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34325521

RESUMO

Background Abdominal aortic aneurysm (AAA) is a life-threatening vascular disorder characterized by chronic inflammation of the aortic wall, which lacks effective pharmacotherapeutic remedies and has an extremely high mortality. Nuclear receptor NR4A1 (Nur77) functions in various chronic inflammatory diseases. However, the influence of Nur77 on AAA has remained unclear. Herein, we sought to determine the effects of Nur77 on the development of AAA. Methods and Results We observed that Nur77 expression decreased significantly in human and mice AAA lesions. Deletion of Nur77 accelerated the development of AAA in mice, as evidenced by increased AAA incidence, abdominal aortic diameters, elastin fragmentation, and collagen content. Consistent with genetic manipulation, pharmacological activation of Nur77 by celastrol showed beneficial effects against AAA. Microscopic and molecular analyses indicated that the detrimental effects of Nur77 deficiency were associated with aggravated macrophage infiltration in AAA lesions and increased pro-inflammatory cytokines secretion and matrix metalloproteinase (MMP-9) expression. Bioinformatics analyses further revealed that LOX-1 was upregulated by Nur77 deficiency and consequently increased the expression of cytokines and MMP-9. Moreover, rescue experiments verified that LOX-1 notably aggravated inflammatory response, an effect that was blunted by Nur77. Conclusions This study firstly demonstrated a crucial role of Nur77 in the formation of AAA by targeting LOX-1, which implicated Nur77 might be a potential therapeutic target for AAA.


Assuntos
Aorta , Inflamação/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Receptores Depuradores Classe E/metabolismo , Animais , Aorta/imunologia , Aorta/patologia , Aneurisma da Aorta Abdominal/metabolismo , Citocinas/metabolismo , Descoberta de Drogas , Elastina/metabolismo , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Knockout , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/deficiência , Tamanho do Órgão , Transdução de Sinais , Remodelação Vascular/imunologia
4.
Chem Biodivers ; 18(8): e2100049, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34118114

RESUMO

We aimed to investigate the impact of apigenin on LOX-1, Bcl-2, and Bax expression in hyperlipidemia rats and explore the possible molecular pathological mechanism of apigenin in improving hyperlipidemia and preventing atherosclerosis. In hyperlipidemia models, the levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-c) and the LOX-1 protein expression were apparently increased (P<0.01), while the high-density lipoprotein cholesterol (HDL-c) levels and the ratio of Bcl-2/Bax were reduced significantly (P<0.01) in comparison with the standard control group. After the treatment of apigenin, the levels of TC, TG, LDL-c, and the LOX-1 protein expression were noticeably decreased (P<0.01), while the levels of HDL-c and the Bcl-2/Bax ratio were increased (P<0.01). The intima was thickened and had protrusions in the hyperlipidemia model group compared to the normal control group. In comparison with the atherosclerosis model group, the degree of aortic lesions in the low-dose, middle-dose, high-dose groups was alleviated. Apigenin can reduce the level of blood lipid, improve hyperlipidemia, and prevent atherosclerosis in hyperlipidemia rats. The molecular mechanism may be related to inhibiting LOX-1 gene expression and increasing the Bcl-2/Bax ratio.


Assuntos
Apigenina/farmacologia , Expressão Gênica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores Depuradores Classe E/metabolismo , Proteína X Associada a bcl-2/metabolismo , Animais , Aorta/metabolismo , Aorta/patologia , Apigenina/uso terapêutico , Colesterol/sangue , Modelos Animais de Doenças , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/patologia , Masculino , Proteínas Proto-Oncogênicas c-bcl-2/genética , Ratos , Ratos Sprague-Dawley , Receptores Depuradores Classe E/genética , Triglicerídeos/sangue , Proteína X Associada a bcl-2/genética
5.
Sci Rep ; 11(1): 11966, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099844

RESUMO

Hyperlipidemia is a risk factor for cardiovascular disease, and miR-21a-5p plays an important role in the occurrence and progression of hyperlipidemia. Here, we aimed to investigate the mechanism of aerobic exercise improved hyperlipidemia through enhancing miR-21a-5p expression. In this study, high-fat/high-cholesterol diet mice received 8 weeks of aerobic exercise intervention, then we collected plasma and liver samples, we found that there had a notable improvement in weight gain, blood lipid level, and liver steatosis in hyperlipidemia mice after 8 weeks of aerobic exercise intervention. Besides, aerobic exercise significantly up-regulated the expression of miR-21a-5p and provoked favorable changes in the expression of target genes. Knockdown of miR-21a-5p resulted in dysregulation of lipid metabolism and increased expression of FABP7, HMGCR, ACAT1, and OLR1. While aerobic exercise could alleviate miR-21a-5p knock-down induced lipid metabolism disorder. Taken together, these results demonstrated that aerobic exercise improved hyperlipidemia through miR-21a-5p-induced inhibition of target genes FABP7, HMGCR, ACAT1, and OLR1.


Assuntos
Hiperlipidemias/terapia , MicroRNAs/metabolismo , Condicionamento Físico Animal/fisiologia , Acetil-CoA C-Acetiltransferase/genética , Acetil-CoA C-Acetiltransferase/metabolismo , Animais , Colesterol/metabolismo , Dieta Hiperlipídica , Proteína 7 de Ligação a Ácidos Graxos/genética , Proteína 7 de Ligação a Ácidos Graxos/metabolismo , Técnicas de Silenciamento de Genes , Hidroximetilglutaril-CoA Redutases/genética , Hidroximetilglutaril-CoA Redutases/metabolismo , Metabolismo dos Lipídeos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores Depuradores Classe E/genética , Receptores Depuradores Classe E/metabolismo
6.
Am J Pathol ; 191(7): 1303-1313, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33964218

RESUMO

Neonatal hypoxic-ischemic encephalopathy (nHIE) is a major neonatal brain injury. Despite therapeutic hypothermia, mortality and sequelae remain severe. The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is associated with the pathophysiology of nHIE. In this study, morphologic change and microglial activation under the nHIE condition and LOX-1 treatment were investigated. The microglial activity and proliferation were assessed with a novel morphologic method, immunostaining, and quantitative PCR in the rat brains of both nHIE model and anti-LOX-1 treatment. Circumference ratio, the long diameter ratio, the cell area ratio, and the roundness of microglia were calculated. The correlation of the morphologic metrics and microglial activation in nHIE model and anti-LOX-1 treated brains was evaluated. LOX-1 was expressed in activated ameboid and round microglia in the nHIE model rat brain. In the evaluation of microglial activation, the novel morphologic metrics correlated with all scales of the nHIE-damaged and treated brains. While the circumference and long diameter ratios had a positive correlation, the cell area ratio and roundness had a negative correlation. Anti-LOX-1 treatment attenuated morphologic microglial activation and proliferation, and suppressed the subsequent production of inflammatory mediators by microglia. In human nHIE, round microglia and endothelial cells expressed LOX-1. The results indicate that LOX-1 regulates microglial activation in nHIE and anti-LOX-1 treatment attenuates brain injury by suppressing microglial activation.


Assuntos
Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/patologia , Microglia/metabolismo , Receptores Depuradores Classe E/metabolismo , Animais , Animais Recém-Nascidos , Encéfalo/metabolismo , Encéfalo/patologia , Humanos , Ratos , Ratos Sprague-Dawley
7.
J Ethnopharmacol ; 276: 114178, 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-33945857

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Si-Miao-Yong-An decoction (SMYAD) is a renowned traditional Chinese medicinal formula. SMYAD was originally recorded in the "Shi Shi Mi Lu", which was edited by medical scientist Chen Shi'duo during the Qing Dynasty. SMYAD has been traditionally used to treat thromboangiitis obliterans. At present, it is mainly used in clinical applications and research of cardiovascular diseases. AIM OF THE STUDY: To explore the effects of SMYAD on the pathological changes of atherosclerosis (AS) and the differentiation of monocytes, macrophages, and regulatory T (Treg) cells in apolipoprotein E knockout (ApoE-/-) mice. MATERIALS AND METHODS: Eight C57BL/6J mice, which were fed with normal diet for 16 weeks, were used as control group. Forty ApoE-/- mice were randomly divided into model group, atorvastatin group, SMYAD low-dose (SMYAD-LD) group, SMYAD medium-dose (SMYAD-MD) group, and SMYAD high-dose (SMYAD-HD) group. ApoE-/- mice were fed with western diet (WD) for 8 weeks, and the drugs were continuously administered for 8 weeks. The levels of serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were measured by the esterase method. Morphological changes of the aortic sinus in mice were observed by hematoxylin-eosin (HE) staining, the lipid infiltration of the aorta and aortic sinus were observed by oil red O staining, and the spleen index was calculated. The proportion of Ly6Chigh and Ly6Clow monocyte subsets, macrophages, and their M1 phenotype, as well as Treg cells in spleen were measured by flow cytometry. The expressions of cluster of differentiation 36 (CD36), scavenger receptor A1 (SRA1), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), F4/80, and fork head frame protein 3 (FOXP3) in aortic sinus were assessed by immunohistochemical staining. The serum levels of oxidized low density lipoprotein (ox-LDL), interleukin-1ß (IL-1ß), IL-18, transforming growth factor-ß (TGF-ß), and IL-10 were measured by enzyme-linked immunosorbent assays (ELISA). RESULTS: Compared with the model group, the level of serum TC and LDL-C decreased in the SMYAD group, the pathological changes of aortic sinus decreased, and lipid infiltration of aorta and aortic sinus also decreased. These decreases were accompanied by a significant downregulation of CD36, SRA1, and LOX-1. Furthermore, the proportions of Ly6Chigh pro-inflammatory monocyte subsets, macrophages, and their M1 phenotypes in spleen decreased significantly, while the proportion of Treg cells increased. In addition, while the expression of F4/80 decreased, the expression of FOXP3 increased in the aorta sinus. The levels of serum pro-inflammatory factors IL-1ß and IL-18 decreased. CONCLUSIONS: SMYAD can improve the pathological changes associated with AS and can inhibit lipid deposition in ApoE-/- mice induced by WD diet. The likely mechanism is the inhibition of the differentiation and recruitment of monocytes and macrophages, the promotion of the differentiation and recruitment of Treg cells, as well as the reduction of the secretion of pro-inflammatory factors.


Assuntos
Apolipoproteínas E/genética , Diferenciação Celular/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Aorta/metabolismo , Aorta/patologia , Antígenos CD36/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Transporte/metabolismo , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Citocinas/sangue , Medicamentos de Ervas Chinesas/uso terapêutico , Fatores de Transcrição Forkhead/metabolismo , Lipoproteínas LDL/sangue , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Placa Aterosclerótica/tratamento farmacológico , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Receptores Acoplados a Proteínas G/metabolismo , Receptores Depuradores Classe E/metabolismo , Baço/efeitos dos fármacos , Baço/metabolismo , Triglicerídeos/sangue
8.
Biochim Biophys Acta Mol Basis Dis ; 1867(7): 166130, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33746034

RESUMO

A high level of low-density lipoprotein cholesterol (LDL) is one of the most important risk factors for coronary artery disease (CAD), the leading cause of death worldwide. However, a low concentration of LDL may be protective. Genome-wide association studies revealed that variation in ADTRP gene increased the risk of CAD. In this study, we found that a low concentration of oxidized-LDL induced the expression of ADTRP. Further analyses showed that knockdown of the expression of LDL receptor genes LDLR, CD36, or LOX-1 significantly downregulated ADTRP expression, whereas overexpression of LDLR/CD36/LOX-1 markedly increased ADTRP expression through the NF-κB pathway. Like ADTRP, LDLR, CD36 and LOX-1 were all involved in endothelial cell (EC) functions relevant to the initiation of atherosclerosis. Downregulation of LDLR/CD36/LOX-1 promoted monocyte adhesion to ECs and transendothelial migration of monocytes by increasing expression of ICAM-1, VCAM-1, E-selectin and P-selectin, decreased EC proliferation and migration, and increased EC apoptosis, thereby promoting the initiation of atherosclerosis. Opposite effects were observed with the overexpression of ADTRP and LDLR/CD36/LOX-1 in ECs. Interestingly, through the NF-κB and AKT pathways, overexpression of ADTRP significantly upregulated the expression of LDLR, CD36, and LOX-1, and knockdown of ADTRP expression significantly downregulated the expression of LDLR, CD36, and LOX-1. These data suggest that ADTRP and LDL receptors LDLR/CD36/LOX-1 positively regulate each other, and form a positive regulatory loop that regulates endothelial cell functions, thereby providing a potential protective mechanism against atherosclerosis. Our findings provide a new molecular mechanism by which deregulation of ADTRP and LDLR/CD36/LOX-1 promote the development of atherosclerosis and CAD.


Assuntos
Aterosclerose/patologia , Antígenos CD36/metabolismo , Células Endoteliais/patologia , Retroalimentação Fisiológica , Proteínas de Membrana/metabolismo , Receptores de LDL/metabolismo , Receptores Depuradores Classe E/metabolismo , Aterosclerose/metabolismo , Antígenos CD36/genética , Adesão Celular , Doença da Artéria Coronariana , Células Endoteliais/metabolismo , Humanos , Proteínas de Membrana/genética , Monócitos/metabolismo , Monócitos/patologia , Receptores de LDL/genética , Receptores Depuradores Classe E/genética , Migração Transendotelial e Transepitelial
9.
Cell Immunol ; 363: 104317, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33714729

RESUMO

Myeloid derived suppressor cells (MDSCs) can be subset into monocytic (M-), granulocytic (G-) or polymorphonuclear (PMN-), and immature (i-) or early MDSCs and have a role in many disease states. In cancer patients, the frequencies of MDSCs can positively correlate with stage, grade, and survival. Most clinical studies into MDSCs have been undertaken with peripheral blood (PB); however, in the present studies, we uniquely examined MDSCs in the spleens and PB from patients with gastrointestinal cancers. In our studies, MDSCs were rigorously subset using the following markers: Lineage (LIN) (CD3, CD19 and CD56), human leukocyte antigen (HLA)-DR, CD11b, CD14, CD15, CD33, CD34, CD45, and CD16. We observed a significantly higher frequency of PMN- and M-MDSCs in the PB of cancer patients as compared to their spleens. Expression of the T-cell suppressive enzymes arginase (ARG1) and inducible nitric oxide synthase (i-NOS) were higher on all MDSC subsets for both cancer patients PB and spleen cells as compared to MDSCs from the PB of normal donors. Similar findings for the activation markers lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), program death ligand 1 (PD-L1) and program cell death protein 1 (PD-1) were observed. Interestingly, the total MDSC cell number exported to clustering analyses was similar between all sample types; however, clustering analyses of these MDSCs, using these markers, uniquely documented novel subsets of PMN-, M- and i-MDSCs. In summary, we report a comparison of splenic MDSC frequency, subtypes, and functionality in cancer patients to their PB by clustering and cytometric analyses.


Assuntos
Células Supressoras Mieloides/metabolismo , Baço/imunologia , Adulto , Idoso , Arginase/metabolismo , Antígeno B7-H1/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Análise por Conglomerados , Feminino , Citometria de Fluxo/métodos , Neoplasias Gastrointestinais/imunologia , Antígenos HLA-DR/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Células Supressoras Mieloides/citologia , Células Supressoras Mieloides/imunologia , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Receptores Depuradores Classe E/metabolismo , Baço/patologia
10.
Oxid Med Cell Longev ; 2021: 8869085, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33574986

RESUMO

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-ß/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-ß/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-ß/SMAD2 and 3 and restored the EndMT in HFD-fed animals. Moreover, PPB showed a restoring effect on HFD-induced hypertension.


Assuntos
Aorta/patologia , Benzofuranos/uso terapêutico , Dieta Hiperlipídica , Endotélio Vascular/patologia , Hipertensão/tratamento farmacológico , Hipertensão/patologia , Mesoderma/patologia , Taninos/uso terapêutico , Animais , Aorta/efeitos dos fármacos , Aorta/fisiopatologia , Benzofuranos/administração & dosagem , Benzofuranos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Espessura Intima-Media Carotídea , Dislipidemias/complicações , Dislipidemias/fisiopatologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Hipertensão/complicações , Hipertensão/fisiopatologia , Lipoproteínas LDL , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Mesoderma/efeitos dos fármacos , Mesoderma/fisiopatologia , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Proteína Quinase C-alfa/metabolismo , Receptores Depuradores Classe E/metabolismo , Proteínas Smad/metabolismo , Taninos/administração & dosagem , Taninos/farmacologia , Fator de Crescimento Transformador beta/metabolismo
11.
Anticancer Agents Med Chem ; 21(6): 803-808, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32951582

RESUMO

BACKGROUND: Selenium Nanoparticles (Se-NPs) are known for their antioxidant and anti-inflammatory activities, which are effective in preventing oxidative damage and improving physiological processes. OBJECTIVES: This study aimed at investigating the effects of biosynthesized Se-NPs on bone marrow-derived Endothelial Progenitor Cells (bone marrow-derived EPCs) and blood-derived endothelial progenitor cells (blood-derived EPCs) isolated from rabbits in vitro. METHODS: The cultured EPCs incubated with biosynthesized Se-NPs at the concentrations of 0.19, 0.38, 0.76, 1.71, 3.42, 7.03, 14.25, 28.50, 57, 114, and 228µg/ml for 48h. After screening the proliferative potential of the Se-NPs by the MTT assay, the best concentrations were selected for Real-Time quantitative Polymerase Chain Reaction (RT-qPCR). Real-time quantification of Vascular Cell Adhesion Molecule 1 (VCAM-1), lectin-like oxidized Low-Density Lipoprotein (LDL) receptor-1 (LOX-1), endothelial Nitric Oxide Synthase (eNOS), and Monocyte Chemoattractant Protein-1 (MCP-1) gene expressions were analyzed by normalizing with Glyceraldehyde- 3-Phosphate Dehydrogenase (GAPDH) as an endogenous reference gene. RESULTS: Blood-derived EPCs and bone marrow-derived EPCs showed morphological differences before treatment in vitro. Se-NPs treated EPCs indicated a significant dose-dependent proliferative activity (p<0.01). In general, the expression levels of VCAM-1, LOX-1, and MCP-1 mRNA were significantly decreased (p<0.01), whereas that of the eNOS expression was significantly increased at the concentrations of 7.3 and 14.25µg/ml (p<0.01). Although the expressions of MCP-1, LOX-1, and eNOS mRNA were decreased at certain concentrations of Se-NPs (p<0.01 and p<0.05, respectively) in the treated bone marrow-derived EPCs, no significant differences were observed in the VCAM-1 mRNA expression levels in bone marrow-derived EPCs compared with the control group (p>0.05). CONCLUSION: This was the first report to demonstrate the effects of Se-NPs on proliferative, anti-oxidative, and anti-inflammatory activities for bone marrow-derived EPCs and blood-derived EPCs. Our findings suggested that Se-NPs could be considered as an effective agent that may ameliorate vascular problems.


Assuntos
Anti-Inflamatórios/química , Antioxidantes/química , Células Progenitoras Endoteliais/efeitos dos fármacos , Nanopartículas/química , Selênio/química , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Células Sanguíneas/citologia , Medula Óssea , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Gliceraldeído-3-Fosfato Desidrogenases/genética , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Humanos , Nanomedicina , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Coelhos , Receptores Depuradores Classe E/genética , Receptores Depuradores Classe E/metabolismo , Selênio/farmacologia , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo
12.
Cell Mol Life Sci ; 78(4): 1523-1544, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32666307

RESUMO

Naturally occurring point mutations in apolipoprotein A-I (apoA-I), the major protein component of high-density lipoprotein (HDL), may affect plasma HDL-cholesterol levels and cardiovascular risk. Here, we evaluated the effect of human apoA-I mutations L144R (associated with low HDL-cholesterol), L178P (associated with low HDL-cholesterol and increased cardiovascular risk) and A164S (associated with increased cardiovascular risk and mortality without low HDL-cholesterol) on the structural integrity and functions of lipid-free and lipoprotein-associated apoA-I in an effort to explain the phenotypes of subjects carrying these mutations. All three mutants, in lipid-free form, presented structural and thermodynamic aberrations, with apoA-I[L178P] presenting the greatest thermodynamic destabilization. Additionally, apoA-I[L178P] displayed reduced ABCA1-mediated cholesterol efflux capacity. When in reconstituted HDL (rHDL), apoA-I[L144R] and apoA-I[L178P] were more thermodynamically destabilized compared to wild-type apoA-I, both displayed reduced SR-BI-mediated cholesterol efflux capacity and apoA-I[L144R] showed severe LCAT activation defect. ApoA-I[A164S] was thermodynamically unaffected when in rHDL, but exhibited a series of functional defects. Specifically, it had reduced ABCG1-mediated cholesterol and 7-ketocholesterol efflux capacity, failed to reduce ROS formation in endothelial cells and had reduced capacity to induce endothelial cell migration. Mechanistically, the latter was due to decreased capacity of rHDL-apoA-I[A164S] to activate Akt kinase possibly by interacting with endothelial LOX-1 receptor. The impaired capacity of rHDL-apoA-I[A164S] to preserve endothelial function may be related to the increased cardiovascular risk for this mutation. Overall, our structure-function analysis of L144R, A164S and L178P apoA-I mutants provides insights on how HDL-cholesterol levels and/or atheroprotective properties of apoA-I/HDL are impaired in carriers of these mutations.


Assuntos
Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Apolipoproteína A-I/genética , Doenças Cardiovasculares/genética , HDL-Colesterol/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Apolipoproteína A-I/metabolismo , Apolipoproteína A-I/ultraestrutura , Doenças Cardiovasculares/patologia , Movimento Celular/genética , HDL-Colesterol/metabolismo , HDL-Colesterol/ultraestrutura , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Fatores de Risco de Doenças Cardíacas , Humanos , Cetocolesteróis/genética , Cetocolesteróis/metabolismo , Lipoproteínas HDL/genética , Lipoproteínas HDL/metabolismo , Lipoproteínas HDL/ultraestrutura , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Proteínas Mutantes/ultraestrutura , Mutação/genética , Receptores Depuradores Classe E/genética , Receptores Depuradores Classe E/metabolismo , Relação Estrutura-Atividade , Termodinâmica
13.
J Nutr Biochem ; 88: 108481, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32853678

RESUMO

Excessive consumption of saturated fat leads to non-alcoholic fatty liver disease (NAFLD), which is attenuated by supplementation of n-3 polyunsaturated fatty acids (PUFAs). Endoplasmic reticulum (ER) stress is crucial in the development of NAFLD, but how high-saturated fat diet (HFD) causes ER stress and NAFLD remains unclear. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is involved in hepatic ER stress. We aimed to explore the roles of LOX-1 in HFD-induced ER stress. Male Sprague-Dawley rats were fed an HFD without or with supplementation of fish oil for 16 weeks. The effects of n-3 PUFAs on hepatic ER stress degrees and the expression levels of LOX-1 were examined. Then human L02 hepatoma cells were treated with palmitate or palmitate and DHA to determine the ER stress and LOX-1 expression levels in vitro. After that the expression of LOX-1 in L02 cells was either knocked-down or overexpressed to analyze the roles of LOX-1 in palmitate-induced ER stress. The feeding of HFD induced NAFLD development and ER stress in the liver, and LOX-1 expressing level, which were all reversed by fish oil supplementation. In vitro, DHA treatment reduced the expression of LOX-1, and palmitate-induced ER stress. SiRNA-mediated knock-down of LOX-1 inhibited palmitate-induced ER stress, whereas overexpression of LOX-1 dramatically induced ER stress in L02 cells.LOX-1 is critical for HFD-induced ER stress, and inhibition of its expression under the treatment of n-3 PUFAs could ameliorate HFD-induced NAFLD.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos/efeitos adversos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores Depuradores Classe E/metabolismo , Animais , Linhagem Celular , Dieta Hiperlipídica/efeitos adversos , Ácidos Docosa-Hexaenoicos/farmacologia , Óleos de Peixe/farmacologia , Humanos , Fígado/metabolismo , Masculino , Hepatopatia Gordurosa não Alcoólica/etiologia , Palmitatos/farmacologia , Ratos , Ratos Sprague-Dawley
14.
Vascul Pharmacol ; 137: 106822, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33232770

RESUMO

BACKGROUND: Tissue 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. METHODS: HUVEC 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. RESULTS: Colchicine 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. CONCLUSIONS: Data 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.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Colchicina/farmacologia , Fibrinolíticos/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Lipoproteínas LDL/farmacologia , Tromboplastina/metabolismo , Células Cultivadas , Fator Xa/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Proteínas I-kappa B/metabolismo , NF-kappa B/metabolismo , Receptores Depuradores Classe E/genética , Receptores Depuradores Classe E/metabolismo , Tromboplastina/genética
15.
Biochim Biophys Acta Gen Subj ; 1865(1): 129758, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33031906

RESUMO

BACKGROUND: Bacterial surface proteins act as potential adhesins or invasins. The GroEL is a signal peptide-free surface expressed protein that aids adhesion in Escherichia coli by binding to LOX-1 receptor of the host cells. Mycobacterium tuberculosis (Mtb) expresses GroEL2 protein, having high level sequence identity with E. coli GroEL. This study investigates the interaction mechanism of GroEL2 protein of Mtb with LOX-1 of macrophages using integrated computational and experimental approach. METHODS: Mtb GroEL2 protein was purified as histidine tagged protein using Ni-NTA chromatography. Confocal and scanning electron microscopies were used to study the uptake of GroEL2 coated fluorescent latex beads through the LOX-1 receptor in RAW264.7 macrophage cell line. Docking studies were performed to understand the interaction between the GroEL2 and LOX-1 proteins. Polyinosinic acid (PIA) was used as a LOX-1 inhibitor in both in silico and in vitro experiments. RESULTS: GroEL2 protein coating enhances uptake of latex beads into macrophages through LOX-1 receptor. LOX-1 inhibitor PIA decreased the uptake of GroEL2 coated latex beads. GroEL2 interacts with the key ligand binding regions of the LOX-1 receptor, such as the basic spine and the saddle hydrophobic patch. PIA molecule destabilized the LOX-1-GroEL2 docked complex. CONCLUSION: Surface associated GroEL2 protein of Mtb is a potential ligand for macrophage LOX-1 receptor. Interaction between GroEL2 and LOX-1 receptor may be utilized by Mtb to gain its intracellular access. GENERAL SIGNIFICANCE: Surface associated GroEL2 of Mtb may bind to the macrophage LOX-1 receptor, enabling the internalization of the bacteria and progression of the infection.


Assuntos
Chaperonina 60/metabolismo , Interações Hospedeiro-Patógeno , Macrófagos/metabolismo , Mycobacterium tuberculosis/fisiologia , Receptores Depuradores Classe E/metabolismo , Tuberculose/metabolismo , Animais , Macrófagos/microbiologia , Camundongos , Simulação de Acoplamento Molecular , Ligação Proteica , Células RAW 264.7 , Tuberculose/microbiologia
16.
Aging (Albany NY) ; 13(1): 437-449, 2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-33290259

RESUMO

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.


Assuntos
Hepatite B Crônica/imunologia , Herpesvirus Humano 4/imunologia , Tolerância Imunológica/imunologia , Células Supressoras Mieloides/imunologia , Carcinoma Nasofaríngeo/imunologia , Neoplasias Nasofaríngeas/imunologia , Recidiva Local de Neoplasia/imunologia , Acetilcisteína/farmacologia , Adulto , Idoso , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/imunologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/imunologia , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Feminino , Sequestradores de Radicais Livres/farmacologia , Hepatite B Crônica/complicações , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Células Supressoras Mieloides/metabolismo , NADPH Oxidase 2/genética , NADPH Oxidase 2/metabolismo , Carcinoma Nasofaríngeo/complicações , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/complicações , Neoplasias Nasofaríngeas/terapia , Prognóstico , Espécies Reativas de Oxigênio/imunologia , Receptores Depuradores Classe E/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Proteínas da Matriz Viral/imunologia
17.
Aging (Albany NY) ; 13(1): 910-932, 2020 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-33290264

RESUMO

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) -1ß 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.


Assuntos
Abietanos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Aorta/efeitos dos fármacos , Aterosclerose/metabolismo , Inflamassomos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/efeitos dos fármacos , Animais , Aorta/metabolismo , Aorta/patologia , Aterosclerose/patologia , Antígenos CD36/efeitos dos fármacos , Antígenos CD36/metabolismo , Dieta Hiperlipídica , Inflamassomos/metabolismo , Lipoproteínas LDL/efeitos dos fármacos , Lipoproteínas LDL/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Knockout para ApoE , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptores Depuradores Classe E/efeitos dos fármacos , Receptores Depuradores Classe E/metabolismo
18.
Arterioscler Thromb Vasc Biol ; 40(12): e322-e335, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33054390

RESUMO

OBJECTIVE: The cAMP second messenger system, a major stress-response pathway, plays essential roles in normal cardiovascular functions and in pathogenesis of heart diseases. Here, we test the hypothesis that the Epac1 (exchange protein directly activated by cAMP 1) acts as a major downstream effector of cAMP signaling to promote atherogenesis and represents a novel therapeutic target. Approach and Results: To ascertain Epac1's function in atherosclerosis development, a triple knockout mouse model (LTe) was generated by crossing Epac1-/- mice with atherosclerosis-prone LDb mice lacking both Ldlr and Apobec1. Deletion of Epac1 led to a significant reduction of atherosclerotic lesion formation as measured by postmortem staining, accompanied by attenuated macrophage/foam cell infiltrations within atherosclerotic plaques as determined by immunofluorescence staining in LTe animals compared with LDb littermates. Primary bone marrow-derived macrophages were isolated from Epac1-null and wild-type mice to investigate the role of Epac1 in lipid uptake and foam cell formation. ox-LDLs (oxidized low-density lipoproteins) stimulation of bone marrow-derived macrophages led to elevated intracellular cAMP and Epac1 levels, whereas an Epac-specific agonist, increased lipid accumulation in wild-type, but not Epac1-null, bone marrow-derived macrophages. Mechanistically, Epac1 acts through PKC (protein kinase C) to upregulate LOX-1 (ox-LDL receptor 1), a major scavenger receptor for ox-LDL uptake, exerting a feedforward mechanism with ox-LDL to increase lipid uptake and propel foam cell formation and atherogenesis. CONCLUSIONS: Our study demonstrates a fundamental role of cAMP/Epac1 signaling in vascular remodeling by promoting ox-LDL uptake and foam cell formation during atherosclerosis lesion development. Therefore, Epac1 represents a promising, unexplored therapeutic target for atherosclerosis.


Assuntos
Aorta Torácica/metabolismo , Doenças da Aorta/metabolismo , Aterosclerose/metabolismo , Células Espumosas/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Placa Aterosclerótica , Receptores Depuradores Classe E/metabolismo , Desaminase APOBEC-1/deficiência , Desaminase APOBEC-1/genética , Animais , Aorta Torácica/patologia , Doenças da Aorta/genética , Doenças da Aorta/patologia , Aterosclerose/genética , Aterosclerose/patologia , AMP Cíclico/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Feminino , Células Espumosas/patologia , Fatores de Troca do Nucleotídeo Guanina/deficiência , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de LDL/deficiência , Receptores de LDL/genética , Sistemas do Segundo Mensageiro , Células THP-1 , Remodelação Vascular
19.
Clin Sci (Lond) ; 134(17): 2295-2313, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32856035

RESUMO

The lectin-like oxidized low-density-lipoprotein (oxLDL) receptor-1 (LOX-1) has been shown to induce angiotensin II (AngII) type 1 receptor (AT1) activation, contributing to vascular dysfunction. Preeclampsia is a pregnancy complication characterized by vascular dysfunction and increased LOX-1 and AT1 activation; however, whether LOX-1 and AT1 activity contributes to vascular dysfunction in preeclampsia is unknown. We hypothesized that increased oxLDL levels during pregnancy lead to LOX-1 activation and subsequent AT1 activation, resulting in vascular dysfunction. Pregnant wild-type (WT) and transgenic LOX-1 overexpressing (LOX-1tg) mice were fed a control diet (CD) or high-cholesterol diet (HCD, to impair vascular function) between gestational day (GD) 13.5-GD18.5. On GD18.5, AngII-induced vasoconstriction and methylcholine (MCh)-induced endothelium-dependent vasodilation responses were assessed in aortas and uterine arteries. HCD decreased fetal weight and increased circulating oxLDL/cholesterol levels in WT, but not in LOX-1tg mice. HCD did not alter AngII responsiveness or AT1 expression in both vascular beds; however, AngII responsiveness and AT1 expression were lower in aortas from LOX-1tg compared with WT mice. In aortas from WT-CD mice, acute oxLDL exposure induced AT1-mediated vasoconstriction via LOX-1. HCD impaired endothelium-dependent vasodilation and increased superoxide levels in WT aortas, but not uterine arteries. Moreover, in WT-CD mice oxLDL decreased MCh sensitivity in both vascular beds, partially via LOX-1. In summary, HCD impaired pregnancy outcomes and vascular function, and oxLDL-induced LOX-1 activation may contribute to vascular dysfunction via AT1. Our study suggests that LOX-1 could be a potential target to prevent adverse outcomes associated with vascular dysfunction in preeclampsia.


Assuntos
Lipoproteínas LDL/farmacologia , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores Depuradores Classe E/metabolismo , Doenças Vasculares/fisiopatologia , Angiotensina II , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Aorta/fisiopatologia , Peso Corporal/efeitos dos fármacos , Colesterol na Dieta , Colina/análogos & derivados , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Feminino , Feto/efeitos dos fármacos , Feto/patologia , Camundongos Transgênicos , Estresse Oxidativo/efeitos dos fármacos , Gravidez , Superóxidos/metabolismo , Artéria Uterina/patologia , Artéria Uterina/fisiopatologia , Doenças Vasculares/patologia , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
20.
Biosci Rep ; 40(8)2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32725144

RESUMO

KRAB domain-associated protein 1 (KAP1) is highly expressed in atherosclerotic plaques. Here, we studied the role of KAP1 in atherosclerosis development using a cell model of endothelial dysfunction induced by oxidative low-density lipoprotein (OxLDL). The phosphorylation and protein levels of KAP1 were similar between OxLDL-treated and non-treated endothelial cells (ECs). KAP1 depletion significantly inhibited the production of OxLDL-enhanced reactive oxygen species and the expression of adhesion molecules in ECs. Treatment with OxLDL promoted the proliferation and migration of ECs, which was also confirmed by the elevated levels of the proliferative markers c-Myc and PCNA, as well as the migratory marker MMP-9. However, these effects were also abrogated by KAP1 depletion. Moreover, the depletion of KAP1 in OxLDL-treated ECs resulted in decreases in the LOX-1 level and increases in eNOS expression. Generally, the data suggest that strategies targeting KAP1 depletion might be particularly useful for the prevention or treatment of atherosclerosis.


Assuntos
Células Endoteliais/efeitos dos fármacos , Inativação Gênica , Lipoproteínas LDL/toxicidade , Receptores Depuradores Classe E/metabolismo , Proteína 28 com Motivo Tripartido/metabolismo , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação , Espécies Reativas de Oxigênio/metabolismo , Receptores Depuradores Classe E/genética , Transdução de Sinais , Proteína 28 com Motivo Tripartido/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...