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1.
Int Heart J ; 60(1): 159-167, 2019 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-30518717

RESUMO

CD36 is one of the important transporters of long-chain fatty acids (LCFAs) in the myocardium. We previously reported that CD36-deficient patients demonstrate a marked reduction of myocardial uptake of LCFA, while myocardial glucose uptake shows a compensatory increase, and are often accompanied by cardiomyopathy. However, the molecular mechanisms and functional role of CD36 in the myocardium remain unknown.The current study aimed to explore the pathophysiological role of CD36 in the heart. Methods: Using wild type (WT) and knockout (KO) mice, we generated pressure overload by transverse aortic constriction (TAC) and analyzed cardiac functions by echocardiography. To assess cardiac hypertrophy and fibrosis, histological and molecular analyses and measurement of ATP concentration in mouse hearts were performed.By applying TAC, the survival rate was significantly lower in KO than that in WT mice. After TAC, KO mice showed significantly higher heart weight-to-tibial length ratio and larger cross-sectional area of cardiomyocytes than those of WT. Although left ventricular (LV) wall thickness in the KO mice was similar to that in the WT mice, the KO mice showed a significant enlargement of LV cavity and reduced LV fractional shortening compared to the WT mice with TAC. A tendency for decreased myocardial ATP concentration was observed in the KO mice compared to the WT mice after TAC operation.These data suggest that the LCFA transporter CD36 is required for the maintenance of energy provision, systolic function, and myocardial structure.


Assuntos
Antígenos CD36/genética , Proteínas de Transporte de Ácido Graxo/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Disfunção Ventricular Esquerda/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Antígenos CD36/fisiologia , Metabolismo Energético/fisiologia , Fibrose , Glucose/metabolismo , Hipertrofia Ventricular Esquerda/complicações , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/patologia , Miócitos Cardíacos/patologia , Pressão/efeitos adversos , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/fisiopatologia , Remodelação Ventricular
2.
Oncol Res ; 27(2): 211-218, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-29540257

RESUMO

Osteosarcomas, especially those with metastatic or unresectable disease, have limited treatment options. The antitumor effects of pharmacologic inhibitors of angiogenesis in osteosarcomas are hampered in patients by the rapid development of tumor resistance, notably through increased invasiveness and accelerated metastasis. Here we demonstrated that thrombospondin 1 (TSP-1) is a potent inhibitor of the growth and metastasis of the osteosarcoma cell line MG-63. Moreover, we demonstrate that upregulation of TSP-1 facilitated expression of vasculostatin in MG-63 cells. In angiogenesis assays, overexpression of TSP-1 inhibited MG-63 cells and induced tube formation of human umbilical vein endothelial cells (HUVECs) in a CD36-dependent fashion. Finally, in xenografted tumors, we observed that TSP-1 overexpression inhibited angiogenesis and tumor growth. These results provided strong evidence for an important role of the TSP-1/CD36/vasculostatin signaling axis in mediating the antiangiogenic activity of osteosarcoma.


Assuntos
Neoplasias Ósseas/patologia , Neovascularização Patológica/etiologia , Osteossarcoma/patologia , Trombospondina 1/fisiologia , Animais , Antígenos CD36/fisiologia , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos BALB C
3.
Arterioscler Thromb Vasc Biol ; 39(2): 263-275, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30567481

RESUMO

Objective- Dysregulated proliferation of vascular smooth muscle cells (VSMC) plays an essential role in neointimal hyperplasia. CD36 functions critically in atherogenesis and thrombosis. We hypothesize that CD36 regulates VSMC proliferation and contributes to the development of obstructive vascular diseases. Approach and Results- We found by immunofluorescent staining that CD36 was highly expressed in human vessels with obstructive diseases. Using guidewire-induced carotid artery injury and shear stress-induced intima thickening models, we compared neointimal hyperplasia in Apoe-/-, Cd36-/- /Apoe-/-, and CD36 specifically deleted in VSMC (VSMC cd36-/-) mice. CD36 deficiency, either global or VSMC-specific, dramatically reduced injury-induced neointimal thickening. Correspondingly, carotid artery blood flow was significantly increased in Cd36-/- /Apoe-/- compared with Apoe-/- mice. In cultured VSMCs from thoracic aorta of wild-type and Cd36-/- mice, we found that loss of CD36 significantly decreased serum-stimulated proliferation and increased cell populations in S phase, suggesting that CD36 is necessary for VSMC S/G2-M-phase transition. Treatment of VSMCs with a TSR (thrombospondin type 1 repeat) peptide significantly increased wild-type, but not Cd36-/- VSMC proliferation. TSR or serum treatment significantly increased cyclin A expression in wild-type, but not in Cd36-/- VSMCs. STAT3 (signal transducer and activator of transcription), which reportedly enhances both VSMC differentiation and maturation, was higher in Cd36-/- VSMCs. CD36 deficiency significantly decreased expression of Col1A1 (type 1 collagen A1 chain) and TGF-ß1 (transforming growth factor beta 1), and increased expression of contractile proteins, including calponin 1 and smooth muscle α actin, and dramatically increased cell contraction. Conclusions- CD36 promotes VSMC proliferation via upregulation of cyclin A expression that contributes to the development of neointimal hyperplasia, collagen deposition, and obstructive vascular diseases.


Assuntos
Antígenos CD36/fisiologia , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/fisiologia , Neointima/patologia , Animais , Antígenos CD36/análise , Proliferação de Células , Ciclina A/análise , Hiperplasia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Transcrição STAT3/fisiologia
4.
J Biomech ; 76: 263-268, 2018 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-29954596

RESUMO

OBJECTIVE: To perform comparative analysis of the role of scavenger receptor CD36 on endothelial vs. sub-endothelial elastic modulus (stiffness) in the aortas of young and aged mice. APPROACHES AND RESULTS: Elastic moduli of endothelial and sub-endothelial layers of freshly isolated mouse aortas were quantified using atomic force microscopy. In young mice (4-6 months old), we found that while endothelial stiffness is markedly reduced in aortas of CD36-/-mice, as compared to WT controls, no difference between CD36-/- and WT aortas is observed in the stiffness of the sub-endothelial layer in denuded arteries. Additionally, inhibition of myosin phosphorylation also decreases the elastic modulus in the EC, but not the sub-EC layer in WT mice. Moreover, inhibiting CD36 mediated uptake of oxLDL in intact WT aortas abrogated oxLDL-induced endothelial stiffening. Further analysis of aged mice (22-25 months) revealed that aging resulted not only in significant stiffening of the denuded arteries, as was previously known, but also a comparable increase in the elastic modulus of the endothelial layer. Most significantly, this stiffening in the EC layer is dependent on CD36, whereas the denuded layer is not affected. CONCLUSIONS: Our results show that the role CD36 in stiffening of cellular components of intact aortas is endothelial-specific and that genetic deficiency of CD36 protects against endothelial stiffening in aged mice. Moreover, these data suggest that endothelial stiffness in intact mouse aortas depends more on the expression of CD36 than on the stiffness of the sub-endothelial layer.


Assuntos
Envelhecimento/fisiologia , Artérias/fisiologia , Antígenos CD36/fisiologia , Células Endoteliais/fisiologia , Animais , Transporte Biológico , Módulo de Elasticidade , Lipoproteínas LDL/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia de Força Atômica , Miosinas/fisiologia
5.
J Biol Chem ; 293(34): 13338-13348, 2018 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-29914985

RESUMO

Obesity-induced metabolic dysfunctions increase the risk for vascular diseases, including type II diabetes and stroke. Managing obesity is of interest to address the worldwide health problem; however, the role of genetic variability in human obesity development and specific targets for obesity-related metabolic disease have not been thoroughly studied. A SNP in the brain-derived neurotropic factor (BDNF) gene that results in the substitution of a valine with a methionine at codon 66 (Val66Met) occurs with a high frequency in humans. This study addressed the effect of genetic variability in developing obesity and the efficacy of the inhibition of cluster of differentiation 36 (CD36), a multifunctional receptor implicated in obesity and insulin resistance, in WT mice and mice with the BDNF Val66Met variant. CD36 inhibition by salvionolic acid B (SAB) in diet-induced obese WT mice reduced visceral fat accumulation and improved insulin resistance. The benefit of SAB was abrogated in CD36 knockout mice, showing the specificity of SAB. In addition, mice with the Val66Met variant in both alleles (BDNFM/M) fed a high-fat diet exhibited extreme obesity with increased CD36 gene and protein levels in macrophages. Chronic SAB treatment in BDNFM/M mice significantly decreased visceral fat accumulation and improved insulin resistance. Notably, the effect of SAB was greater in the extremely obese BDNFM/M mice compared with the WT mice. The study demonstrated a link between BDNF Val66Met and elevated CD36 expression and suggested that CD36 inhibition may be a potential strategy to improve metabolic dysfunctions and to normalize risk factors for vascular diseases in the obese population.


Assuntos
Benzofuranos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/genética , Antígenos CD36/antagonistas & inibidores , Resistência à Insulina , Gordura Intra-Abdominal , Mutação , Obesidade/prevenção & controle , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Antígenos CD36/fisiologia , Diferenciação Celular , Dieta Hiperlipídica/efeitos adversos , Masculino , Metionina/química , Metionina/genética , Metionina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Valina/química , Valina/genética , Valina/metabolismo
6.
EMBO Rep ; 19(6)2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29777051

RESUMO

Cellular senescence is a unique cell fate characterized by stable proliferative arrest and the extensive production and secretion of various inflammatory proteins, a phenomenon known as the senescence-associated secretory phenotype (SASP). The molecular mechanisms responsible for generating a SASP in response to senescent stimuli remain largely obscure. Here, using unbiased gene expression profiling, we discover that the scavenger receptor CD36 is rapidly upregulated in multiple cell types in response to replicative, oncogenic, and chemical senescent stimuli. Moreover, ectopic CD36 expression in dividing mammalian cells is sufficient to initiate the production of a large subset of the known SASP components via activation of canonical Src-p38-NF-κB signaling, resulting in the onset of a full senescent state. The secretome is further shown to be ligand-dependent, as amyloid-beta (Aß) is sufficient to drive CD36-dependent NF-κB and SASP activation. Finally, loss-of-function experiments revealed a strict requirement for CD36 in secretory molecule production during conventional senescence reprogramming. Taken together, these results uncover the Aß-CD36-NF-κB signaling axis as an important regulator of the senescent cell fate via induction of the SASP.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Antígenos CD36/fisiologia , Senescência Celular/fisiologia , NF-kappa B/metabolismo , Antígenos CD36/genética , Células Cultivadas , Senescência Celular/genética , Fibroblastos/metabolismo , Humanos , Mutação com Perda de Função , Transdução de Sinais
7.
Diabetes ; 67(7): 1272-1284, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29748289

RESUMO

During reduced energy intake, skeletal muscle maintains homeostasis by rapidly suppressing insulin-stimulated glucose utilization. Loss of this adaptation is observed with deficiency of the fatty acid transporter CD36. A similar loss is also characteristic of the insulin-resistant state where CD36 is dysfunctional. To elucidate what links CD36 to muscle glucose utilization, we examined whether CD36 signaling might influence insulin action. First, we show that CD36 deletion specific to skeletal muscle reduces expression of insulin signaling and glucose metabolism genes. It decreases muscle ceramides but impairs glucose disposal during a meal. Second, depletion of CD36 suppresses insulin signaling in primary-derived human myotubes, and the mechanism is shown to involve functional CD36 interaction with the insulin receptor (IR). CD36 promotes tyrosine phosphorylation of IR by the Fyn kinase and enhances IR recruitment of P85 and downstream signaling. Third, pretreatment for 15 min with saturated fatty acids suppresses CD36-Fyn enhancement of IR phosphorylation, whereas unsaturated fatty acids are neutral or stimulatory. These findings define mechanisms important for muscle glucose metabolism and optimal insulin responsiveness. Potential human relevance is suggested by genome-wide analysis and RNA sequencing data that associate genetically determined low muscle CD36 expression to incidence of type 2 diabetes.


Assuntos
Antígenos CD36/fisiologia , Glucose/metabolismo , Insulina/metabolismo , Músculo Esquelético/metabolismo , Receptor de Insulina/metabolismo , Animais , Antígenos CD36/genética , Células CHO , Metabolismo dos Carboidratos/genética , Células Cultivadas , Cricetinae , Cricetulus , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Humanos , Resistência à Insulina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/genética
8.
Compr Physiol ; 8(2): 493-507, 2018 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-29687890

RESUMO

Several proteins have been implicated in fatty acid (FA) transport by enterocytes including the scavenger receptor CD36 (SR-B2), the scavenger receptor B1 (SR-B1) a member of the CD36 family and the FA transport protein 4 (FATP4). Here, we review the regulation of enterocyte FA uptake and its function in lipid absorption including prechylomicron formation, assembly and transport. Emphasis is given to CD36, which is abundantly expressed along the digestive tract of rodents and humans and has been the most studied. We also address the pleiotropic functions of CD36 that go beyond lipid absorption and metabolism to include recent evidence of its impact on intestinal homeostasis and barrier maintenance. Areas of progress involving contribution of membrane phospholipid remodeling and of cytosolic FA-binding proteins, FABP1 and FABP2 to fat absorption will be covered. © 2018 American Physiological Society. Compr Physiol 8:493-507, 2018.


Assuntos
Antígenos CD36/fisiologia , Absorção Intestinal/fisiologia , Metabolismo dos Lipídeos/fisiologia , Animais , Transporte Biológico/fisiologia , Quilomícrons/biossíntese , Sistema Digestório/metabolismo , Enterócitos/metabolismo , Ácidos Graxos/metabolismo , Homeostase/fisiologia , Humanos , Fosfolipídeos/metabolismo
9.
Biochem J ; 475(7): 1253-1265, 2018 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-29523748

RESUMO

The cardioprotective lipoprotein HDL (high-density lipoprotein) prevents myocardial infarction and cardiomyocyte death due to ischemia/reperfusion injury. The scavenger receptor class B, type 1 (SR-B1) is a high-affinity HDL receptor and has been shown to mediate HDL-dependent lipid transport as well as signaling in a variety of different cell types. The contribution of SR-B1 in cardiomyocytes to the protective effects of HDL on cardiomyocyte survival following ischemia has not yet been studied. Here, we use a model of simulated ischemia (oxygen and glucose deprivation, OGD) to assess the mechanistic involvement of SR-B1, PI3K (phosphatidylinositol-3-kinase), and AKT in HDL-mediated protection of cardiomyocytes from cell death. Neonatal mouse cardiomyocytes and immortalized human ventricular cardiomyocytes, subjected to OGD for 4 h, underwent substantial cell death due to necrosis but not necroptosis or apoptosis. Pretreatment of cells with HDL, but not low-density lipoprotein, protected them against OGD-induced necrosis. HDL-mediated protection was lost in cardiomyocytes from SR-B1-/- mice or when SR-B1 was knocked down in human immortalized ventricular cardiomyocytes. HDL treatment induced the phosphorylation of AKT in cardiomyocytes in an SR-B1-dependent manner. Finally, chemical inhibition of PI3K or AKT or silencing of either AKT1 or AKT2 gene expression abolished HDL-mediated protection against OGD-induced necrosis of cardiomyocytes. These results are the first to identify a role of SR-B1 in mediating the protective effects of HDL against necrosis in cardiomyocytes, and to identify AKT activation downstream of SR-B1 in cardiomyocytes.


Assuntos
Antígenos CD36/fisiologia , Glucose/deficiência , Lipoproteínas HDL/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Oxigênio/toxicidade , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Necrose , Fosforilação , Transdução de Sinais
10.
J Clin Endocrinol Metab ; 103(5): 1856-1866, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29546316

RESUMO

Context: Abnormal fatty acid (FA) metabolism contributes to diabetes and cardiovascular disease. The FA receptor CD36 has been linked to risk of metabolic syndrome. In rodents CD36 regulates various aspects of fat metabolism, but whether it has similar actions in humans is unknown. We examined the impact of a coding single-nucleotide polymorphism in CD36 on postprandial hormone and bile acid (BA) responses. Objective: To examine whether the minor allele (G) of coding CD36 variant rs3211938 (G/T), which reduces CD36 level by ∼50%, influences hormonal responses to a high-fat meal (HFM). Design: Obese African American (AA) women carriers of the G allele of rs3211938 (G/T) and weight-matched noncarriers (T/T) were studied before and after a HFM. Setting: Two-center study. Participants: Obese AA women. Intervention: HFM. Main Outcome Measures: Early preabsorptive responses (10 minutes) and extended excursions in plasma hormones [C-peptide, insulin, incretins, ghrelin fibroblast growth factor (FGF)19, FGF21], BAs, and serum lipoproteins (chylomicrons, very-low-density lipoprotein) were determined. Results: At fasting, G-allele carriers had significantly reduced cholesterol and glycodeoxycholic acid and consistent but nonsignificant reductions of serum lipoproteins. Levels of GLP-1 and pancreatic polypeptide (PP) were reduced 60% to 70% and those of total BAs were 1.8-fold higher. After the meal, G-allele carriers displayed attenuated early (-10 to 10 minute) responses in insulin, C-peptide, GLP-1, gastric inhibitory peptide, and PP. BAs exhibited divergent trends in G allele carriers vs noncarriers concomitant with differential FGF19 responses. Conclusions: CD36 plays an important role in the preabsorptive hormone and BA responses that coordinate brain and gut regulation of energy metabolism.


Assuntos
Ácidos e Sais Biliares/sangue , Antígenos CD36/genética , Jejum/sangue , Hormônios/sangue , Absorção Intestinal/fisiologia , Adulto , Afro-Americanos/genética , Antígenos CD36/fisiologia , Estudos de Casos e Controles , Metabolismo Energético/genética , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
11.
Toxicol Lett ; 290: 123-132, 2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29571893

RESUMO

Previous studies have indicated that the main air pollutant fine particulate matter (≤2.5 µm; PM2.5) exposure is associated with the development of atherosclerosis. Although the mechanism is not fully illustrated, the inflammatory responses play an important role. The present study aimed to explore whether PM2.5-exacerbated atherosclerosis was mediated by the cooperation of cluster of differentiation 36 (CD36) and nucleotide-binding oligomerization domain-like receptor protein (NLRP3) inflammasome in apolipoprotein E-/- (ApoE-/-) mice. Thirty-two ApoE-/- mice were randomly divided into two groups. One group was fed with high fat chow (HFC) for 10 weeks to establish atherosclerotic model, and the other was fed with normal chow (NC). From week 11, the mice were exposed to concentrated PM2.5 (PM) or filtered air (FA) using Shanghai Meteorological and Environmental Animal Exposure System for 16 weeks. In both NC and HFC groups, PM2.5 exposure induced the formation of atherosclerosis plaque. Similarly, PM mice appeared higher lipid content in the aortic root than that in the FA mice. Compared with the FA mice, PM mice appeared a decrease in high density lipoprotein-cholesterol (HDL-C) and apolipoprotein A1 along with an increase in apolipoprotein B, low density lipoprotein-cholesterol (LDL-C) and oxidized low-density lipoprotein (ox-LDL). Moreover, PM2.5 exposure induced increase of CD36 in serum and aorta. In both NC and HFC groups, NLRP3 inflammasome activation-related indicators were activated or increased in the aorta of the PM mice when compared with the FA mice. The cooperation of CD36 and NLRP3 inflammasome activation may be the potential mechanisms linkixposed to concentrated PM2.5 (PM) or filtered air (FA) using Shanghai Meteorological and Environmental Animal Exposure System for 16 weeks. In both NC and HFC groups, PM2.5 exposure induced the formation of atherosclerosis plaque. Similarly, PM mice appeared higher lipid content in the aortic root than that in the FA mice. Compared with the FA mice, PM mice appeared a decrease in high density lipoprotein-cholesterol (HDL-C) and apolipoprotein A1 along with an increase in apolipoprotein B, low density lipoprotein-cholesterol (LDL-C) and oxidized low-density lipoprotein (ox-LDL). Moreover, PM2.5 exposure induced increase of CD36 in serum and aorta. In both NC and HFC groups, NLRP3 inflammasome activation-related indicators were activated or increased in the aorta of the PM mice when compared with the FA mice. The cooperation of CD36 and NLRP3 inflammasome activation may be the potential mechanisms linking air pollution and HFC-induced atherosclerosis even in the mice with NC intake.


Assuntos
Poluição do Ar/efeitos adversos , Apolipoproteínas E/fisiologia , Aterosclerose/etiologia , Antígenos CD36/fisiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Material Particulado/toxicidade , Animais , Caspase 1/metabolismo , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Interleucina-18/sangue , Lipoproteínas LDL/sangue , Masculino , Camundongos , Espécies Reativas de Oxigênio/metabolismo
12.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 33(8): 1079-1086, 2017 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-28871950

RESUMO

Objective To investigate the effect of microRNA-155 on inflammatory response and lipid uptake of macrophages after the cells are stimulated by ox-LDL and its potential mechanism. Methods Macrophage RAW264.7 cells were treated with 0, 25, 50 and 100 µg/mL ox-LDL for 24 hours or with 50 µg/mL ox-LDL for 0, 6, 12, 24 hours. The level of miR-155 was evaluated in all above samples through real-time quantitative PCR. In our research, RAW264.7 cells were divided into six groups: control group, ox-LDL group, ox-LDL/negative control group, ox-LDL/anti-miR-155 group, ox-LDL/shRNA negative control group and ox-LDL/PPARγ-shRNA group. Oil red O staining was used to observe lipid uptake in the cells. Filipin staining was used to evaluate the cellular uptake of ox-LDL. Cholesterol testing was performed to examine the levels of total cholesterol (TC) and free cholesterol (FC). Real-time quantitative PCR was done to detect the expressions of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and IL-6 mRNAs. According to study purpose, we explored the potential mechanisms of miR-155 inhibitor (including control group, ox-LDL group, ox-LDL/negative control group and ox-LDL/miR-155 inhibitor group), miR-155 mimic (including negative control group and miR-155 mimic group), and PPARγ shRNA (including control group, ox-LDL group, ox-LDL/shRNA negative control group and ox-LDL/PPARγ shRNA group) in ox-LDL-treated RAW264.7 cells through evaluating the expressions of p-STAT3, PPARγ, CD36 and NF-κBp65 using Western blotting. Results Ox-LDL stimulation increased the relative expression of miR-155 in a dose- and time-dependent manner. Through oil red O staining, Filipin staining, cholesterol testing and real-time PCR experiment, we found the relative absorbance, levels of TC and FC, filipin fluorescence intensity, and levels of TNF-α, IL-1ß and IL-6 mRNAs were significantly lower in ox-LDL/anti-miR-155 group than in ox-LDL and ox-LDL/negative control group. Similarly, the relative absorbance, levels of TC and FC, filipin fluorescence intensity and levels of TNF-α, IL-1ß and IL-6 mRNAs were significantly lower in ox-LDL/ PPARγ shRNA group than in ox-LDL group and ox-LDL/shRNA negative control group. The expressions of p-STAT3, PPARγ, CD36 and NF-κBp65 proteins were suppressed in ox-LDL/anti-miR-155 group as compared with ox-LDL group and ox-LDL/negative control group. Similarly, p-STAT3, PPARγ, CD36 and NF-κBp65 protein levels decreased in ox-LDL/PPARγ shRNA as compared with ox-LDL/vector group. Moreover, p-STAT3, PPARγ, CD36 and NF-κBp65 protein levels were higher in miR-155 mimic group than in negative control group. Conclusion Mediated by PPARγ, miR-155 induced inflammation response and lipid uptake of macrophages via STAT3/NF-κB signal pathway and CD36.


Assuntos
Inflamação/etiologia , Metabolismo dos Lipídeos , Macrófagos/metabolismo , MicroRNAs/fisiologia , Animais , Antígenos CD36/fisiologia , Células Cultivadas , Colesterol/metabolismo , Citocinas/genética , Lipoproteínas LDL/farmacologia , Camundongos , NF-kappa B/fisiologia , PPAR gama/fisiologia , Fator de Transcrição STAT3/fisiologia
13.
Adv Clin Exp Med ; 26(4): 717-722, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28691408

RESUMO

Atherosclerosis is a progressive, chronic inflammation in artery walls. Oxidized low density lipoproteins (ox-LDL) play an important role in atherosclerotic plaque formation. ox-LDL are taken up by macrophages mainly through scavenger receptors, among which CD36 is considered to be the most important. Animal studies have shown that crossing atherogenic mice with a strain lacking the expression of CD36 prevented the development of atherosclerosis despite a diet rich in saturated LCFA. In humans, autopsy studies performed in obese patients have demonstrated increased expression of CD36 receptor on macrophages, comprised within atherosclerotic plaques. Until recently it had been believed that CD36 is a major player in atherosclerosis progression in humans. However, recent studies challenge this conviction, showing increased incidence of coronary heart disease in the subgroup of patients with decreased expression of CD36. This article reviews the role of CD36 receptor in the development of atherosclerosis. The authors also discuss current possibilities to interfere with CD36, their potential benefits and hazards.


Assuntos
Aterosclerose/etiologia , Antígenos CD36/fisiologia , Arginina/farmacologia , Antígenos CD36/química , Antígenos CD36/genética , Regulação da Expressão Gênica , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Tiazolidinedionas/farmacologia
14.
Biomed Res ; 38(3): 207-213, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28637956

RESUMO

Cluster of differentiation 36 (CD36) is a broadly expressed transmembrane receptor that has multiple ligands. It has been found to occur abundantly on the surface of the olfactory epithelium in mice and postulated to play a role in mammalian olfaction. However, there have been no ethological analyses of the mammalian behaviour showing CD36 involvement in the olfactory perception of a distinct odour-active volatile compound. In this study, we aimed to assess whether mammals perceive oleic aldehyde, an odour-active volatile that serves as a potential CD36 ligand, and if so, whether CD36 is involved in the sensing by following measurements using CD36-knockout mice and their wild-type littermates. In a two-bottle choice test, wild-type mice, but not CD36-knockout mice, discriminated a sucrose solution containing oleic aldehyde from the sucrose solution alone. To assess the importance of the olfactory system in the oleic aldehyde perception, we conducted an exploration test where the animals could rely primarily on the odour of test volatiles for recognition. We found that the wild-type, but not CD36-knockout mice, were aware of the compound. Our results provide behavioural evidence that CD36 plays a role in the perception of specific odour-active volatile compounds in the nasal cavity.


Assuntos
Antígenos CD36/fisiologia , Ácido Oleico/fisiologia , Olfato , Animais , Feminino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Cavidade Nasal/fisiologia , Percepção Olfatória
15.
Malar J ; 16(1): 193, 2017 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-28486940

RESUMO

BACKGROUND: Plasmodium falciparum-infected erythrocytes sequester in the microcirculation due to interaction between surface-expressed parasite proteins and endothelial receptors. Endothelial cells are covered in a carbohydrate-rich glycocalyx that shields against undesired leukocyte adhesion. It was investigated if the cellular glycocalyx affects the binding of P. falciparum-infected erythrocytes to CD36 in vitro. METHODS: Glycocalyx growth was followed in vitro by using azido sugars and cationized ferritin detecting O-glycoproteins and negatively charged proteoglycans, respectively. P. falciparum (clone FCR3/IT) was selected on Chinese hamster ovary (CHO) cells transfected with human CD36. Cytoadhesion to CHO CD36 at 1-4 days after seeding was quantified by using a static binding assay. RESULTS: The glycocalyx thickness of CHO cells increased during 4 days in culture as assessed by metabolic labelling of glycans with azido sugars and with electron microscopy studying the binding of cationized ferritin to cell surfaces. The functional importance of this process was addressed in binding assays by using CHO cells transfected with CD36. In parallel with the maturation of the glycocalyx, antibody-binding to CD36 was inhibited, despite stable expression of CD36. P. falciparum selected for CD36-binding recognized CD36 on CHO cells on the first day in culture, but the binding was lost after 2-4 days. CONCLUSION: The endothelial glycocalyx affects parasite cytoadhesion in vitro, an effect that has previously been ignored. The previously reported loss of glycocalyx during experimental malaria may play an important role in the pathogenesis of malaria complications by allowing the close interaction between infected erythrocytes and endothelial receptors.


Assuntos
Antígenos CD36/fisiologia , Eritrócitos/parasitologia , Glicocálix/parasitologia , Plasmodium falciparum/fisiologia , Animais , Células CHO , Cricetinae , Cricetulus , Células Endoteliais/fisiologia , Humanos , Malária Falciparum/fisiopatologia
16.
Biochimie ; 136: 27-32, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28238842

RESUMO

Understanding the mechanisms governing food intake is a public health issue given the dramatic rise of obesity over the world. The overconsumption of tasty energy-dense foods rich in lipids is considered to be one of the nutritional causes of this epidemic. Over the last decade, the identification of fatty acid receptors in strategic places in the body (i.e. oro-intestinal tract and brain) has provided a major progress in the deciphering of regulatory networks involved in the control of dietary intake. Among these lipid sensors, CD36/SR-B2 appears to play a significant role since this membrane protein, known to bind long-chain fatty acid with a high affinity, was specifically found both in enterocytes and in a subset of taste bud cells and entero-endocrine cells. After a short overview on CD36/SR-B2 structure, function and regulation, this mini-review proposes to analyze the key findings about the role of CD36/SR-B2 along of the tongue-gut axis in relation to appetite control. In addition, we discuss whether obesogenic diets might impair lipid sensing mediated by CD36/SR-B2 along this axis.


Assuntos
Apetite/fisiologia , Antígenos CD36/fisiologia , Trato Gastrointestinal/fisiologia , Língua/fisiologia , Animais , Preferências Alimentares , Humanos , Lipídeos/fisiologia , Obesidade/fisiopatologia
17.
Minerva Med ; 108(1): 1-12, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27706112

RESUMO

BACKGROUND: TRPV4, a non-selective cation channel, is involved in lipometabolism and atherosclerosis. However, whether TRPV4 participates in oxygenized low density lipoprotein (oxLDL)-induced foam cell formation remains unknown. The present study investigates the effect of oxLDL on the expression of TRPV4 in macrophages and its underlying mechanisms. METHODS: The expression of TRPV4 in RAW264.7 and phorbol-12-myristate-13-acetate (PMA) induced U937, THP-1 cells was detected by immunofluorescence, and western blot was used to detect the TRPV4 expression before and after PMA induction. Each cell line was divided into three groups, including control group, native low-density lipoprotein (nLDL) (100 µg/mL) group and oxLDL (100µg/mL) group; the expression of TRPV4 in each group was measured using immunohistochemistry and western blot. TRPV4 protein expression was detected by western blot after RAW 264.7 cells were treated with 0, 0.01 µM, 0.1 µM and 1 µM T0070907 or preincubated with 0.1 µM T0070709 for 1 h before incubation with oxLDL for 24 h. RESULTS: In all macrophage cell lines, TRPV4 was widely expressed. PMA increased TRPV4 expression in U937 and THP-1 cells. There was no significant difference in TRPV4 expression in the nLDL group compared to that in the control group; however a significant reduction in TRPV4 expression was detected in the oxLDL group compared to that in the control and nLDL groups using measurements obtained from both immunohistochemistry and western blot. The PPARγ inhibitor T0070907 enhanced the basal expression of TRPV4 and protected RAW264.7 cells from oxLDL-induced TRPV4 down-regulation. CONCLUSIONS: This study revealed that TRPV4 was widely expressed in macrophages and that oxLDL could induce the down-regulation of TRPV4 expression through its actions on PPARγ. This study may serve as an important first step for further investigation into the roles of TRPV4 in macrophage-derived foam cell formation in atherosclerosis.


Assuntos
Lipoproteínas LDL/farmacologia , Macrófagos/efeitos dos fármacos , PPAR gama/fisiologia , Animais , Benzamidas/farmacologia , Antígenos CD36/fisiologia , Relação Dose-Resposta a Droga , Humanos , Macrófagos/metabolismo , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , PPAR delta/efeitos dos fármacos , PPAR gama/antagonistas & inibidores , Piridinas/farmacologia , Células RAW 264.7 , Acetato de Tetradecanoilforbol/farmacologia , Células U937
18.
Sci Rep ; 6: 27460, 2016 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-27270216

RESUMO

Fructose consumption induces metabolic syndrome to increase cardiovascular disease risk. Cinnamaldehyde and allopurinol possess anti-oxidative and anti-inflammatory activity to relieve heart injury in metabolic syndrome. But the mechanisms of fructose-induced cardiac injury, and cardioprotective effects of cinnamaldehyde and allopurinol are not completely understood. In this study, fructose-fed rats displayed metabolic syndrome with elevated serum ox-LDL, cardiac oxidative stress, inflammation and fibrosis. Scavenger receptor CD36, Toll-like receptor 4 (TLR4), TLR6, IL-1R-associated kinase 4/1 (IRAK4/1), nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome, interleukin-1ß, transforming growth factor-ß (TGF-ß), drosophila mothers against DPP homolog (Smad) 2/3 phosphorylation and Smad4 were increased in animal and H9c2 cell models. These pathological processes were further evaluated in ox-LDL or fructose-exposed H9c2 cells pretreated with ROS scavenger and CD36 specific inhibitor, or IRAK1/4 inhibitor, and transfected with CD36, NLRP3, or IRAK4/1 siRNA, demonstrating that NLPR3 inflammasome activation through CD36-mediated TLR4/6-IRAK4/1 signaling may promote cardiac inflammation and fibrosis. Cinnamaldehyde and allopurinol reduced cardiac oxidative stress to suppress NLPR3 inflammasome activation and TGF-ß/Smads signaling by inhibiting CD36-mediated TLR4/6-IRAK4/1 signaling under fructose induction. These results suggest that the blockage of CD36-mediated TLR4/6-IRAK4/1 signaling to suppress NLRP3 inflammasome activation by cinnamaldehyde and allopurinol may protect against fructose-induced cardiac inflammation and fibrosis.


Assuntos
Acroleína/análogos & derivados , Alopurinol/farmacologia , Antígenos CD36/fisiologia , Fibrose/prevenção & controle , Inflamassomos/metabolismo , Miocardite/prevenção & controle , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Acroleína/farmacologia , Animais , Fibrose/metabolismo , Masculino , Miocardite/metabolismo , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley
19.
Inflammation ; 39(3): 1225-37, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27121266

RESUMO

Gamma-linolenic acid (GLA) and linoleic acid (LA), which are both n-6 unsaturated fatty acids, play vital roles in lipopolysaccharide (LPS)-induced inflammation. The multi-functional protein scavenger receptor CD36 has also been shown to participate in inflammation. However, the molecular mechanisms underlying the interactions between CD36 and GLA or LA in LPS-induced inflammation remain unclear. We used small interfering RNA and adenoviral systems to manipulate CD36 expression in primary goat mammary gland epithelial cells (pGMECs), and the results showed that nuclear factor kappa B (NF-κB) levels were significantly decreased by CD36 receptor signaling following treatment with GLA but not LA. GLA inhibited NF-κB activation in LPS-induced pGMECs. However, silencing CD36 or deleting its fatty acid-binding domain blocked the anti-inflammatory effects of GLA, resulting in an increase in NF-κB activation and disrupting its localization during LPS-induced inflammation. The activity of the cytokines IL-1ß, IL-6, and TNF-α, which act downstream of NF-κB, was also modulated when CD34 expression was manipulated by the addition of GLA in LPS-induced pGMECs. Our data suggest that GLA, but not LA, may interact with the CD36 fatty acid-binding domain to regulate the activation and localization of NF-κB in LPS-induced pGMECs.


Assuntos
Antígenos CD36/fisiologia , Células Epiteliais/metabolismo , Inflamação/etiologia , Glândulas Mamárias Animais/patologia , NF-kappa B/metabolismo , Ácido gama-Linolênico/farmacologia , Animais , Antígenos CD36/antagonistas & inibidores , Células Cultivadas , Citocinas/metabolismo , Células Epiteliais/patologia , Feminino , Cabras , Inflamação/patologia , Lipopolissacarídeos , RNA Interferente Pequeno/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ácido alfa-Linoleico/farmacologia
20.
Biomed Res ; 36(5): 303-11, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26522147

RESUMO

CD36 is a broadly expressed transmembrane protein that engages multiple ligands, including polar lipids. This protein is thought to even contribute to the chemosensory detection of long-chain fatty acids in the oral cavity of rodents. In this study, we assessed whether animals consciously perceive a ligand of CD36, 1-(palmitoyl)-2-(5-keto-6-octanedioyl)phosphatidylcholine (KOdiA-PC), and if so, whether CD36 is involved in sensing the oxidised phospholipid species. We found that mice avoided or hesitated to ingest fluids containing KOdiA-PC, suggesting a conscious perception of the lipid in the animals. We assessed the involvement and role of CD36 in the KOdiA-PC perception by comparing the behavioural responses of wild-type and CD36-deficient mice to the test fluids, and provided evidence that the protein could play a role in sensing a lower level of the lipid. We also found that transection of the olfactory nerve of wild-type mice resulted in an inability to perceive KOdiA-PC, suggesting the significance of olfactory system in the lipid sensing. Our findings, coupled with the recent finding of CD36 expression in the mouse olfactory epithelium, led us to predict that the site of CD36 action in the KOdiA-PC sensing plausibly lies within the nasal cavity of the animal.


Assuntos
Antígenos CD36/fisiologia , Fosfolipídeos/metabolismo , Animais , Antígenos CD36/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxirredução
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