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1.
J Cell Mol Med ; 25(20): 9851-9862, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34523794

RESUMO

Adiponectin is an adipocyte-derived hormone, which is closely associated with the development of Alzheimer's disease (AD) and has potential preventive and therapeutic significance. In the present study, we explored the relationship between adiponectin and circadian rhythm disorder in AD, the effect of adiponectin on the abnormal expression of Bmal1 mRNA/protein induced by amyloid-ß protein 31-35 (Aß31-35), and the underlying mechanism of action. We found that adiponectin-knockout mice exhibited amyloid-ß deposition, circadian rhythm disorders and abnormal expression of Bmal1. Adiponectin ameliorated the abnormal expression of the Bmal1 mRNA/protein caused by Aß31-35 by inhibiting the activity of glycogen synthase kinase 3ß (GSK3ß). These results suggest that adiponectin deficiency could induce circadian rhythm disorders and abnormal expression of the Bmal1 mRNA/protein, whilst exogenous administration of adiponectin may improve Aß31-35-induced abnormal expression of Bmal1 by inhibiting the activity of GSK3ß, thus providing a novel idea for the treatment of AD.

2.
Curr Med Chem ; 2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34525914

RESUMO

Hyperinsulinism-hyperammonemia syndrome (HHS) is a rare disease characterized by recurrent hypoglycemia and persistent elevation of plasma ammonia, and it can lead to severe epilepsy and permanent brain damage. It has been demonstrated that functional mutations of glutamate dehydrogenase (GDH), an enzyme in the mitochondrial matrix, are responsible for the HHS. Thus, GDH has become a promising target for the small molecule therapeutic intervention of HHS. Several medicinal chemistry studies are currently aimed at GDH, however, to date, none of the compounds reported has been entered clinical trials. This perspective summarizes the progress in the discovery and development of GDH inhibitors, including the pathogenesis of HHS, potential binding sites, screening methods, and research models. Future therapeutic perspectives are offered to provide a reference for discovering potent GDH modulators and encourage additional research that will provide more comprehensive guidance for drug development.

3.
J Cell Mol Med ; 25(17): 8464-8478, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34322993

RESUMO

Cardiomyocytes autophagy is essential for maintaining cardiac function. Our previous studies have found that ß1 -adrenergic receptor autoantibody (ß1 -AA) induced the decreased myocardial autophagic flux, which resulted in cardiomyocyte death and cardiac dysfunction. And other studies demonstrated that ß1 -AA induced the decrease of AMPK phosphorylation, the key hub of autophagy pathway, while adiponectin up-regulated autophagic flux mediated by AMPK. However, it is not clear whether adiponectin improves the inhibition of myocardial autophagic flux induced by ß1 -AA by up-regulating the level of AMPK phosphorylation. In this study, it has been confirmed that ß1 -AA induced the decrease of AMPK phosphorylation level in both vivo and vitro. Moreover, pretreatment of cardiomyocytes with AMPK inhibitor Compound C could further reduce the autophagic flux induced by ß1 -AA. Adiponectin deficiency could aggravate the decrease of myocardial AMPK phosphorylation level, autophagic flux and cardiac function induced by ß1 -AA. Further, exogenous adiponectin could reverse the decline of AMPK phosphorylation level and autophagic flux induced by ß1 -AA and even reduce cardiomyocyte death. While pretreated with the Compound C, the adiponectin treatment did not improve the decreased autophagosome formation, but still improved the decreased autophagosome clearance induced by ß1 -AA in cardiomyocytes. This study is the first time to confirm that ß1 -AA could inhibit myocardial autophagic flux by down-regulating AMPK phosphorylation level. Adiponectin could improve the inhibition of myocardial autophagic flux induced by ß1 -AA partly dependent on AMPK, so as to provide an experimental basis for the treatment of patients with ß1 -AA-positive cardiac dysfunction.

4.
J Immunol Res ; 2021: 1815098, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34307691

RESUMO

Adiponectin is a small peptide secreted and a key component of the endocrine system and immune system. Although globular adiponectin protects myocardial ischemia/reperfusion-induced cardiomyocyte injury, the protective mechanisms remain largely unresolved. Using a neonatal rat ventricular myocyte hypoxia/reoxygenation model, we investigated the role of its potential mechanisms of necroptosis in globular adiponectin-mediated protection in hypoxia/reoxygenation-induced cardiomyocyte injury as compared to apoptosis. We found that globular adiponectin treatment attenuated cardiomyocyte injury as indicated by increased cell viability and reduced lactate dehydrogenase release following hypoxia/reoxygenation. Immunofluorescence staining and Western blotting demonstrated that both necroptosis and apoptosis were triggered by hypoxia/reoxygenation and diminished by globular adiponectin. Necrostatin-1 (RIP1-specific inhibitor) and Z-VAD-FMK (pan-caspase inhibitor) only mimicked the inhibition of necroptosis and apoptosis, respectively, by globular adiponectin in hypoxia/reoxygenation-treated cardiomyocytes. Globular adiponectin attenuated reactive oxygen species production, oxidative damage, and p38MAPK and NF-κB signaling, all important for necroptosis and apoptosis. Collectively, our study suggests that globular adiponectin inhibits hypoxia/reoxygenation-induced necroptosis and apoptosis in cardiomyocytes probably by reducing oxidative stress and interrupting p38MAPK signaling.

6.
Hum Cell ; 34(1): 49-59, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32959354

RESUMO

ATF3 (activating transcription factor 3) is a member of the mammalian activation transcription factor/cAMP-responsive element-binding (CREB) family. It plays a role in inflammation and innate immunity, and suggests that ATF3 is associated with atherosclerosis. In our study, we analyzed datasets of atherosclerosis from the NCBI-GEO (Gene Expression Omnibus) database and found that expression levels of ATF3 were lower in macrophages from ruptured atherosclerotic plaques than from stable atherosclerotic plaques. Expression levels of ATF3 correlated with the stability of atherosclerotic plaques. KEGG analysis of different expression genes (DEGs) between ruptured and stable atherosclerotic plaques was performed by Metascape database. The PI3K-AKT pathway may be a potential pathway of the formation of ruptured atherosclerotic plaques. High-fat diet-induced atherosclerosis apoE-/- mice were divided into two groups: a model group and an ATF3 overexpression (OE)-group. Tests on atherosclerotic plaques in the aortic root suggested that absence of ATF3 and increase of macrophages may be risk factors for the formation of ruptured atherosclerotic plaques. We found decreased areas of lesions in aortic roots and branches of aortic arch, as well as increased lesional content of macrophages as well as TUNEL-positive areas. Consistent with these results, we found reduced degradation and incidence of elastic plate cracks accompanied by suppressed MMPs expression and transduction pathway protein PI3K/AKT activation. These data suggest that ATF3 is a signaling molecule that mediates the progression and stability of atherosclerotic plaques. ATF3 could be a potential new biomarker for the prognosis of atherosclerosis and may be a therapeutic target to reduce atherosclerosis.

7.
Mol Med Rep ; 23(2)2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33300086

RESUMO

Intermedin (IMD) is a calcitonin/calcitonin­related peptide that elicits cardioprotective effects in a variety of heart diseases, such as cardiac hypertrophy and heart failure. However, the molecular mechanism of IMD remains unclear. The present study investigated the effects of IMD on neonatal rat ventricular myocytes treated with thapsigargin. The results of the present study demonstrated that thapsigargin induced apoptosis in cardiomyocytes in a dose­ and time­dependent manner. Thapsigargin induced endoplasmic reticulum stress, as determined by increased expression levels of 78­kDa glucose­regulated protein, C/EBP­homologous protein and caspase­12, which were dose­dependently attenuated by pretreatment with IMD. In addition, IMD treatment counteracted the thapsigargin­induced suppression of sarco/endoplasmic reticulum Ca2+­ATPase (SERCA) activity and protein expression levels, and cytoplasmic Ca2+ overload. IMD treatment also augmented the phosphorylation of phospholamban, which is a crucial regulator of SERCA. Additionally, treatment with the protein kinase A antagonist H­89 inhibited the IMD­mediated cardioprotective effects, including SERCA activity restoration, anti­Ca2+ overload, endoplasmic reticulum stress inhibition and antiapoptosis effects. In conclusion, the results of the present study suggested that IMD may protect cardiomyocytes against thapsigargin­induced endoplasmic reticulum stress and the associated apoptosis at least partly by activating the protein kinase A/SERCA pathway.


Assuntos
Adrenomedulina/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Neuropeptídeos/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Tapsigargina/farmacologia , Adrenomedulina/genética , Animais , Sinalização do Cálcio/genética , Proteínas Quinases Dependentes de AMP Cíclico/genética , Estresse do Retículo Endoplasmático/genética , Feminino , Masculino , Neuropeptídeos/genética , Ratos , Ratos Sprague-Dawley , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética
8.
Cell Chem Biol ; 27(12): 1483-1499.e9, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33186540

RESUMO

H2S-producing enzymes in bacteria have been shown to be closely engaged in the process of microbial survival and antibiotic resistance. However, no inhibitors have been discovered for these enzymes, e.g., 3-mercaptopyruvate sulfurtransferase (MST). In the present study, we identified several classes of inhibitors for Escherichia coli MST (eMST) through high-throughput screening of ∼26,000 compounds. The thiazolidinedione-type inhibitors were found to selectively bind to Arg178 and Ser239 residues of eMST but hardly affected human MST. Moreover, the pioglitazone of this class concentration dependently accumulates the 3-mercaptopyruvate substrate and suppresses the H2S and reactive sulfane sulfur products in bacteria. Importantly, pioglitazone could potentiate the level of reactive oxygen species in cellulo and consequently enhance the antimicrobial effects of gentamicin and macrophages in culture. This study has identified the bioactive inhibitor of eMST, paving the way for the pharmacological targeting of eMST to synergistically control the survival of E. coli.

9.
Med Sci Monit ; 26: e924016, 2020 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-32772038

RESUMO

BACKGROUND The objective of the study was to explore the role of long non-coding RNA SNHG8 (lncRNA SNHG8) in myocardial infarction (MI) and the related mechanism of action. MATERIAL AND METHODS In vitro model of MI was established by hypoxia induction in cardiomyocyte line H9c2 cells. H9c2 cells were transfected with control-plasmid, SNHG8-plasmid, control-shRNA and SNHG8-shRNA. Quantitative real-time polymerase chain reaction (qRT-PCR) assay was performed to measure transfection efficiency. Creatine kinase-muscle/brain (CK-MB) release, cardiac troponin 1 (cTnI) release and mitochondria viability were detected by using related detection kits. MTT (3-(45)-dimethylthiahiazo (-z-y 1)-35-diphenytetrazoliumromide) assay was used to detect cell viability and flow cytometry analysis was used to detect cell apoptosis. Western blot assay was performed to measure protein expression of cleaved-Caspase3, p-p65 and p65. Enzyme-linked immunosorbent assay (ELISA) and qRT-PCR assay were performed to detect expression of interleukin (IL)-1ß, tumor necrosis factor (TNF)-alpha and IL-6. RESULTS LncRNA SNHG8 was overexpressed in hypoxia-induced cardiomyocytes. SNHG8-plasmid increased lncRNA SNHG8 expression, CK-MB release, cTnI release, and mitochondria viability in hypoxia-induced H9c2 cells. In addition, SNHG8-plasmid reduced cell viability, induced cell apoptosis, and increased expression of cleaved-caspase3, IL-1ß, TNF-alpha, IL-6, and p-p65 in hypoxia-induced H9c2 cells, while the effects of SNHG8-shRNA were opposite. CONCLUSIONS We demonstrated that lncRNA SNHG8 affected myocardial infarction by affecting hypoxia-induced cardiomyocyte injury via regulation of the NF-kappaB pathway.


Assuntos
Hipóxia Celular/genética , Dano ao DNA/genética , Infarto do Miocárdio/genética , Miócitos Cardíacos/patologia , RNA Longo não Codificante/fisiologia , Animais , Apoptose , Biomarcadores/metabolismo , Linhagem Celular , Sobrevivência Celular , Técnicas de Silenciamento de Genes , Mediadores da Inflamação/metabolismo , Infarto do Miocárdio/metabolismo , Ratos
10.
Biochem Cell Biol ; 98(5): 583-590, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32413267

RESUMO

Research has shown that some circular RNAs (circRNA) are abnormally expressed in the process of myocardial fibrosis, but the mechanism behind this was unknown. In the process of inducing cardiac fibroblast (CF) activation with TGF-ß1 or Ang II, the expression of circRNA circ_BMP2K and miR-455-3p were significantly inhibited, whereas the expression of SUMO1 was promoted. The results from our dual luciferase reporter gene assays, RIP assays, and pull-down assays show that miR-455-3p directly binds circ_BMP2K, thereby mutually promoting their expression levels. SUMO1 is a target gene of miR-455-3p, and circ_BMP2K enhances the inhibitory effects of miR-455-3p on the expression of SUMO1. Further study showed that both circ_BMP2K and miR-455-3p inhibited the expression of alpha-SMA as well as type I and type III collagen, whereas SUMO1 promoted their expression, and miR-455-3p inhibitors or overexpression of SUMO1 reversed the effects of circ_BMP2K and miR-455-3p. Circ_BMP2K and miR-455-3p inhibits cell proliferation and migration and promotes the apoptosis of CFs, but SUMO1 has the opposite effects; miR-455-3p inhibitors or overexpression of SUMO1 reverses the effects of circ_BMP2K and miR-455-3p. Thus, circ_BMP2K promotes the expression of miR-455-3p, down-regulates the expression of SUMO1, and finally, inhibits the activation, growth, and migration of CFs. These results could provide important therapeutic targets and a theoretical basis for regulating the process of myocardial fibrosis.


Assuntos
Fibroblastos/metabolismo , MicroRNAs/metabolismo , RNA Circular/metabolismo , Proteína SUMO-1/metabolismo , Movimento Celular , Proliferação de Células , Células Cultivadas , Fibroblastos/patologia , Humanos , MicroRNAs/genética , RNA Circular/genética , Proteína SUMO-1/genética
11.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1862(9): 929-938, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28602962

RESUMO

ATP-binding cassette transporter A1 (ABCA1) plays a crucial role in reverse cholesterol transport and exhibits anti-atherosclerosis effects. Some microRNAs (miRs) regulate ABCA1 expression, and recent studies have shown that miR-20a/b might play a critical role in atherosclerotic diseases. Here, we attempted to clarify the potential contribution of miR-20a/b in post-transcriptional regulation of ABCA1, cholesterol efflux, and atherosclerosis. We performed bioinformatics analysis and found that miR-20a/b was highly conserved and directly bound to ABCA1 mRNA with low binding free energy. Luciferase-reporter assay also confirmed that miR-20a/b significantly reduced luciferase activity associated with the ABCA1 3' untranslated region reporter construct. Additionally, miR-20a/b decreased ABCA1 expression, which, in turn, decreased cholesterol efflux and increased cholesterol content in THP-1 and RAW 264.7 macrophage-derived foam cells. In contrast, miR-20a/b inhibitors increased ABCA1 expression and cholesterol efflux, decreased cholesterol content, and inhibited foam-cell formation. Consistent with our in vitro results, miR-20a/b-treated ApoE-/- mice showed decreased ABCA1expression in the liver and reductions of reverse cholesterol transport in vivo. Furthermore, miR-20a/b regulated the formation of nascent high-density lipoprotein and promoted atherosclerotic development, whereas miR-20a/b knockdown attenuated atherosclerotic formation. miR-20 is a new miRNA capable of targeting ABCA1 and regulating ABCA1 expression. Therefore, miR-20 inhibition constitutes a new strategy for ABCA1-based treatment of atherosclerosis.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Colesterol/metabolismo , MicroRNAs/metabolismo , Processamento Pós-Transcricional do RNA/fisiologia , Regiões 3' não Traduzidas , Animais , Aterosclerose/metabolismo , Linhagem Celular , Células Espumosas/metabolismo , Regulação da Expressão Gênica/fisiologia , Células HEK293 , Humanos , Lipoproteínas HDL/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7
12.
Exp Ther Med ; 13(6): 2757-2762, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28587337

RESUMO

The objective of the present study was to investigate the effect of adiponectin (APN) on macrophage reverse cholesterol transport (RCT) in adiponectin-/- knockout mice (APN-/-mice) and its possible anti-atherosclerotic mechanism. A total of 30 male APN-/-mice were randomly divided into the control group and four intervention groups. The intervention groups were treated with intraperitoneal injections of APN, at doses of 50, 150, 200 and 250 µg/(kg/day), respectively, for 4 weeks. The control group received normal saline. After 4 weeks, serum lipid levels were measured, the degree of severity of atherosclerotic lesions was observed by light microscopy, the 3H-TC (APN-/-mice treated with intraperitoneal injections of 3H-TC-labeled macrophages) radioactivity in serum, liver, and feces, and the expression of ABCA1 mRNA and protein in liver were determined. Compared with the control group, serum triglycerides, total cholesterol, and low-density lipoproteins levels in the intervention groups were significantly decreased, while high-density lipoprotein was increased. The severity of aortic atherosclerotic lesions in the intervention groups was milder than in the control group, which had obvious aortic atherosclerotic lesions, large lipid deposition on vessel walls, and the formation of atheromatous plaques. In the intervention groups, serum 3H-TC content was significantly decreased (P<0.05), but the 3H-TC content in liver and feces was significantly increased (P<0.05). The levels of ABCA1 mRNA in liver of the intervention groups were significantly increased in a dose-dependent manner. In conclusion, APN can promote RCT and intracellular cholesterol efflux by upregulating the expression of ABCA1, to delay the occurrence and development of atherosclerosis.

13.
Cell Physiol Biochem ; 38(5): 1906-14, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27160732

RESUMO

BACKGROUND/AIMS: To detect the changes of high density lipoprotein (HDL) and its subtypes in serum of patients with coronary heart disease (CHD). METHODS: 337 hospitalized patients were selected from our hospital during August, 2014 - January, 2015, and divided into CHD group (n = 190) and control group (n = 127). Lipoprint lipoprotein analyzer was used to classify low density lipoprotein (LDL) particle size and its sub-components, as well as HDL particle size and its sub-components. The changes of the subtypes in patients with CHD were statistically analyzed. The possible mechanism was explored. RESULTS: (1) Compared with the control group, the concentration of HDL in CHD patients reduced, HDLL significantly decreased (P < 0.001), while HDLS increased (P < 0.001); (2) In the patients with HDL less than 1.04 mmol/L among CHD, all HDL subtypes reduced, but HDLL had the most significant decreased; (3) HDL and all HDL subtypes were positively correlated with apolipoprotein A-I (apoA-I), of which, HDLL had the biggest correlation with apoA-I (P < 0.001); (4) HDL subtypes had good correlation with HDL, of which, HDLM had a maximum correlation with HDL (P < 0.001). CONCLUSION: HDL maturation disorders existed in the serum of CHD patients, HDLL may be protected factor for CHD, whose decrease was closely related wit the risk increase of CHD. The cardiovascular protection function of HDLL may be related with apoA-I content.


Assuntos
Doença da Artéria Coronariana/patologia , Idoso , Apolipoproteína A-I/sangue , Índice de Massa Corporal , Estudos de Casos e Controles , Doença da Artéria Coronariana/sangue , Feminino , Humanos , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Masculino , Pessoa de Meia-Idade , Tamanho da Partícula , Triglicerídeos/sangue
14.
Mol Med Rep ; 13(6): 5021-8, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27121797

RESUMO

Platelet activation is important in hypertension­induced cardiac inflammation and fibrosis. P-selectin expression significantly (P<0.05) increases when platelets are activated during hypertension. Although P­selectin recruits leukocytes to sites of inflammation, the role of P­selectin in cardiac inflammation and fibrosis remains to be elucidated. The present study aimed to investigate whether platelet­derived P­selectin promotes hypertensive cardiac inflammation and fibrosis. P­selectin knockout (P­sel KO) mice and wild­type (WT) C57BL/6 littermates were infused with angiotensin II (Ang II) at 1,500 ng/kg/min for 7 days and then cross­transplanted with platelets originating from either WT or P­sel KO mice. P­selectin expression was increased in the myocardium and plasma of hypertensive mice, and the P­sel KO mice exhibited significantly (P<0.05) reduced cardiac fibrosis. The fibrotic areas were markedly smaller in the hearts of P­sel KO mice compared with WT mice, as assessed by Masson's trichrome staining. In addition, α­smooth muscle actin and transforming growth factor ß1 (TGF­ß1) expression levels were decreased in the P­sel KO mice, as assessed by immunohistochemistry. Following platelet transplantation into P­sel KO mice, the number of Mac­2 (galectin­3)­ and TGF­ß1­positive cells was increased in mice that received WT platelets compared with those that received P­sel KO platelets, and the mRNA expression levels of collagen I and TGF­ß1 were also increased. The results from the present study suggest that activated platelets secrete P­selectin to promote cardiac inflammation and fibrosis in Ang II­induced hypertension.


Assuntos
Angiotensina II/metabolismo , Plaquetas/metabolismo , Miocardite/etiologia , Miocardite/metabolismo , Selectina-P/metabolismo , Ativação Plaquetária , Angiotensina II/sangue , Animais , Plaquetas/efeitos dos fármacos , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Fibrose , Expressão Gênica , Hipertensão/induzido quimicamente , Hipertensão/complicações , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Knockout , Miocardite/diagnóstico , Miocárdio/metabolismo , Miocárdio/patologia , Selectina-P/genética
15.
Mol Med Rep ; 12(4): 5335-41, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26165515

RESUMO

Induction of oxidative stress has a causal role in atherosclerosis. The aim of the present study was to examine the role of lectin­like oxidized low­density lipoprotein receptor­1 (LOX­1) in oxidized low­density lipoprotein (OxLDL)­induced oxidative stress in atherosclerosis. Small interfering RNA (siRNA) technology was employed to decrease the expression of LOX­1 in mouse RAW264.7 macrophages and the effects of LOX­1 silencing on OxLDL­induced reactive oxygen species (ROS) generation and NADPH oxidase (NOX) expression were investigated. The in vivo effects of reducing LOX­1 were also examined in a mouse model (ApoE­/­) of high­fat diet­induced atherosclerosis. Compared with the control cells, OxLDL exposure led to a significant (P<0.05) increase in the intracellular levels of malondialdehyde and ROS and a significant decrease in the activity of superoxide dismutase. Delivery of LOX­1­targeting siRNA significantly (P<0.05) reversed the alterations in oxidative stress parameters induced by OxLDL. LOX­1 silencing downregulated the expression of NOX2, Rac1, p47phox and p22phox and impaired the activation of mitogen­activated protein kinases in OxLDL­treated cells. Adenoviral delivery of LOX­1 siRNA caused a significant increase in the size of the fibrous cap and a decrease in the macrophage content in lesions, compared with the control mice. Western blot analysis demonstrated that the protein expression levels of NOX1, Rac1, p47phox and p22phox in aortic lesions were significantly lower in the LOX­1 siRNA group than in the control group. LOX­1 is implicated in OxLDL­induced oxidative stress of macrophages in atherosclerosis, which in part, involves the regulation of NADPH oxidases.


Assuntos
Aterosclerose/metabolismo , Aterosclerose/patologia , Lipoproteínas LDL/metabolismo , Macrófagos/metabolismo , Estresse Oxidativo , Receptores Depuradores Classe E/metabolismo , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/genética , Linhagem Celular , Grupo dos Citocromos b/genética , Grupo dos Citocromos b/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Inativação Gênica , Lipídeos/sangue , Lipoproteínas LDL/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , NADPH Oxidase 2 , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Placa Aterosclerótica/genética , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , RNA Interferente Pequeno/genética , Receptores Depuradores Classe E/genética , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismo
16.
Int J Clin Exp Pathol ; 8(3): 2545-54, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26045760

RESUMO

OBJECTIVE: This study aims to explore the mechanism of globular adiponectin inhibiting vascular calcification. METHODS: We established drug-induced rat vascular calcification model, globular adiponectin was given to observe the effect of globular Adiponectin on the degree of calcification. The markers of vascular calcification and apoptosis were also investigated. Meanwhile, the in vitro effect of globular Adiponectin on vascular calcification was also evaluated using primary cultured rat vascular smooth muscle cells. RESULTS: We found that globular adiponectin could inhibit drug-induced rat vascular calcification significantly in vivo. The apoptosis of vascular smooth muscle cells was also reduced. The possible mechanism could be the down-regulation of endoplasmic reticulum stress by globular adiponectin. Experiments in primary cultured vascular smooth muscle cells also confirmed that globular adiponectin could reduce cell apoptosis to suppress vascular calcification via inhibition of endoplasmic reticulum stress. CONCLUSIONS: This study confirmed that globular adiponectin could suppress vascular calcification; one of the mechanisms could be inhibition of endoplasmic reticulum stress to reduce cell apoptosis. It could provide an effective method in the therapy of vascular calcification-associated diseases.


Assuntos
Adiponectina/metabolismo , Apoptose/fisiologia , Estresse do Retículo Endoplasmático/fisiologia , Músculo Liso Vascular/patologia , Calcificação Vascular/fisiopatologia , Adiponectina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa
17.
Cell Physiol Biochem ; 35(6): 2472-82, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25967876

RESUMO

BACKGROUND/AIMS: Atherosclerosis is a chronic inflammatory disease. Intracellular adhesion molecule-1 (ICAM-1), vascular cellular adhesion molecule-1 (VCAM-1), and monocyte chemoattractant protein-1 (MCP-1) play important roles in inflammatory processes. P38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB signaling regulate ICAM-1, VCAM-1, and MCP-1 expression. Angiotensin (Ang) II upregulates ICAM-1, VCAM-1, and MCP-1 expression through the P38 MAPK and NF-κB pathways. Ang-(1-7) may oppose the actions of Ang II. We investigated whether Ang-(1-7) prevents Ang II-induced ICAM-1, VCAM-1, and MCP-1 expression in human umbilical vein endothelial cells (HUVECs). METHODS: ICAM-1, VCAM-1, and MCP-1 expression was estimated by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA); P38, NF-κB, and p-IκB-α expression was estimated by western blotting. RESULTS: Ang-(1-7) inhibited Ang II-induced ICAM-1, VCAM-1, and MCP-1 expression and secretion in HUVECs. Ang II sharply increased P38 MAPK phosphorylation, which was inhibited by pretreatment with Ang-(1-7). Moreover, Ang-(1-7) significantly inhibited Ang II-induced IκB-α phosphorylation and NF-κB P65 nuclear translocation. The MAS receptor antagonist A-779 abolished the suppressive effects of Ang-(1-7). CONCLUSION: Ang-(1-7) attenuates Ang II-induced ICAM-1, VCAM-1, and MCP-1 expression via the MAs receptor by suppressing the P38 and NF-κB pathways in HUVECs. Ang-(1-7) might delay the progression of inflammatory diseases, including atherosclerosis.


Assuntos
Angiotensina II/farmacologia , Angiotensina I/farmacologia , Quimiocina CCL2/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , NF-kappa B/metabolismo , Fragmentos de Peptídeos/farmacologia , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Proteínas I-kappa B/metabolismo , Inibidor de NF-kappaB alfa , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
18.
Int J Clin Exp Pathol ; 8(1): 450-7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25755733

RESUMO

ATP-binding cassette transporter A1 (ABCA1) plays a crucial role in reverse cholesterol transport and anti-atherosclerosis. Liver X receptor alpha (LXRα) can stimulate cholesterol efflux through ABCA1. It has been well known that adiponectin has cardiovascular protection. In this study, we attempted to clarify the effect of adiponectin on expression of ABCA1, and explored the role of LXRα in the regulation of ABCA1 in RAW 264.7 macrophages. Our results showed that adiponectin increased ABCA1 expression at both the mRNA and protein levels in a dose-dependent and time-dependent manner. Consequently, adiponectin promoted cholesterol efflux and decreased cholesterol content in RAW 264.7 macrophages. Moreover, adiponectin up-regulated the expression of LXRα in a dose-dependent and time-dependent manner in RAW 264.7 macrophages. LXRα small interfering RNA completely abolished the promotion effects of adiponectin. In summary, adiponectin up-regulates ABCA1 expression via the LXRα pathway in RAW 264.7 macrophages. This novel insight could prove useful for developing new treatment strategies for cardiovascular diseases.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Adiponectina/farmacologia , Macrófagos/efeitos dos fármacos , Receptores Nucleares Órfãos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Transportador 1 de Cassete de Ligação de ATP/genética , Animais , Linhagem Celular , Colesterol/metabolismo , Relação Dose-Resposta a Droga , Receptores X do Fígado , Macrófagos/metabolismo , Camundongos , RNA Interferente Pequeno
19.
Mol Med Rep ; 12(1): 1387-92, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25779847

RESUMO

Angiotensin II (Ang II) and Ang-(1-7) are key effector peptides of the renin-angiotensin system. The present study aimed to investigate the effects of Ang-(1-7) on Ang II-stimulated cholesterol efflux and the associated molecular mechanisms. Differentiated THP-1 macrophages were treated with Ang II (1 µM) and/or Ang-(1-7) (10 and 100 nM) for 24 h and the cholesterol efflux and gene expression levels were assessed. Pharmacological inhibition of peroxisome proliferator-activated receptor (PPAR)γ and mitogen-activated protein kinases (MAPKs) were performed to identify the signaling pathways involved. The results demonstrated that Ang II significantly inhibited the cholesterol efflux from cholesterol-loaded THP-1 macrophages. Treatment with Ang-(1-7) led to a dose-dependent restoration of cholesterol efflux in the Ang II-treated cells. The co-treatment with Ang-(1-7) and Ang II significantly increased the expression levels of adenosine triphosphate (ATP)-binding cassette (ABC)A1 and ABCG1 compared with treatment with Ang II alone. This was coupled with increased expression levels of PPARγ and liver X receptor (LXR)α. The pharmacological inhibition of PPARγ significantly (P<0.05) eliminated the Ang-(1-7)-mediated induction of ABCA1 and ABCG1 mRNA expression. Treatment with Ang-(1-7) caused the inactivation of c-Jun N-terminal kinases (JNK) and p38 MAPK signaling in the Ang II-treated THP-1 macrophages. In addition, the inhibition of JNK or p38 MAPK signaling using specific pharmacological inhibitors mimicked the Ang-(1-7)-induced expression of PPARγ and LXRα. In conclusion, the data demonstrated that treatment with Ang-(1-7) promoted cholesterol efflux in Ang II-treated THP-1 macrophages, partly through inactivation of p38 and JNK signaling and by inducing the expression of PPARγ and LXRα. Ang (1-7) may, therefore, have therapeutic benefits for the treatment of atherosclerosis.


Assuntos
Aterosclerose/genética , Colesterol/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/biossíntese , Receptores Nucleares Órfãos/biossíntese , Proteínas Quinases p38 Ativadas por Mitógeno/biossíntese , Transportador 1 de Cassete de Ligação de ATP/biossíntese , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/biossíntese , Angiotensina I/administração & dosagem , Angiotensina II/administração & dosagem , Aterosclerose/tratamento farmacológico , Aterosclerose/patologia , Regulação Enzimológica da Expressão Gênica , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Receptores X do Fígado , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Receptores Nucleares Órfãos/genética , PPAR gama/antagonistas & inibidores , Fragmentos de Peptídeos/administração & dosagem , RNA Mensageiro/biossíntese , Sistema Renina-Angiotensina , Proteínas Quinases p38 Ativadas por Mitógeno/genética
20.
Clin Exp Pharmacol Physiol ; 41(12): 1023-30, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25225013

RESUMO

Adenosine triphosphate-binding cassette transporter A1 (ABCA1) and ABCG1 play crucial roles in reverse cholesterol transport, and have anti-atherosclerosis effects, and liver X receptor alpha (LXRα) can stimulate cholesterol efflux through these transporters. Angiotensin (Ang)-(1-7) can protect endothelial cells, inhibit smooth muscle cell growth, ameliorate inflammation and exert anti-atherosclerotic effects. In the present study, we attempted to clarify the effect of Ang-(1-7) on expression of ABCA1 and ABCG1, and explored the role of LXRα in the regulation of ABCA1 and ABCG1 in THP-1 macrophages that had been incubated with angiotensin-II (AngII). Ang-(1-7) increased ABCA1 and ABCG1 expression in a concentration-dependent manner at both the mRNA and protein levels, promoted cholesterol efflux, and decreased cholesterol content in THP-1 macrophages treated with AngII. Furthermore, Ang-(1-7) upregulated the expression of LXRα in a concentration-dependent manner in these cells. LXRα small interfering RNA, as well as the Mas receptor antagonist A-779, completely abolished these effects of Ang-(1-7). In summary, Ang-(1-7) upregulates ABCA1 and ABCG1 expression in THP-1 macrophages treated with AngII through the Mas receptor, via the LXRα pathway. This novel insight into the molecular mechanism underlying Ang-(1-7) and AngII interaction could prove useful for developing new strategies for treatment of cardiovascular diseases.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/genética , Angiotensina I/genética , Receptores Nucleares Órfãos/genética , Fragmentos de Peptídeos/genética , Proteínas Proto-Oncogênicas/genética , Receptores Acoplados a Proteínas G/genética , Transdução de Sinais/genética , Regulação para Cima/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Aterosclerose/genética , Linhagem Celular Tumoral , Colesterol/metabolismo , Humanos , Receptores X do Fígado , Macrófagos/metabolismo , Proteínas de Membrana Transportadoras/genética , RNA Mensageiro/genética , RNA Interferente Pequeno/genética
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