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1.
Int J Mol Sci ; 22(7)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805303

RESUMO

Atherosclerotic plaque is the pathophysiological basis of important and life-threatening diseases such as myocardial infarction. Although key aspects of the process of atherosclerotic plaque development and progression such as local inflammation, LDL oxidation, macrophage activation, and necrotic core formation have already been discovered, many molecular mechanisms affecting this process are still to be revealed. This minireview aims to describe the current directions in research on atherogenesis and to summarize selected studies published in recent years-in particular, studies on novel cellular pathways, epigenetic regulations, the influence of hemodynamic parameters, as well as tissue and microorganism (microbiome) influence on atherosclerotic plaque development. Finally, some new and interesting ideas are proposed (immune cellular heterogeneity, non-coding RNAs, and immunometabolism) which will hopefully bring new discoveries in this area of investigation.


Assuntos
Aterosclerose/fisiopatologia , Placa Aterosclerótica/fisiopatologia , Animais , Aterosclerose/genética , Aterosclerose/metabolismo , Epigênese Genética , Humanos , Inflamação , Lipoproteínas LDL , Ativação de Macrófagos , Placa Aterosclerótica/genética , Placa Aterosclerótica/metabolismo
2.
Life Sci ; 274: 119249, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33652034

RESUMO

BACKGROUND: Accumulating evidence has reported the role of microRNA (miR) on atherosclerosis (AS), while it is unclear about the relationship between microRNA-125b-5p (miR-125b-5p) and AS. Thus, the object of this study was to investigate the impact of exosomal miR-125b-5p targeting mitogen-activated protein 4 kinase 4 (Map4k4) on AS plaque formation. METHODS: The AS model was established using a high fat diet in ApoE-/- mice. Mouse bone marrow-derived mesenchymal stem cells (BMSCs) were selected and BMSC-exosomes (BMSC-EXO) were extracted and then identified. The targeted relationship between miR-125b-5p and Map4k4 was tested. BMSC-EXO were modified with miR-125b-5p- and Map4k4-related sequences to interfere with AS mice. MiR-125b-5p and Map4k4 expression in AS tissues were tested. The inflammation-related indices, blood lipid, plaque area, apoptosis index, MMP-9 and α-SMA expression in mice with AS were measured. RESULTS: BMSCs and BMSC-EXO were successfully isolated. MiR-125b-5p was down-regulated and Map4k4 was up-regulated in aorta tissues from ApoE-/- mice after AS modeling, verses those from C57BL/6 mice without modeling. MiR-125b-5p targeted Map4k4. BMSC-EXO increased miR-125b-5p expression and decreased Map4k4 expression. BMSC-EXO/up-regulated miR-125b-5p and down-regulated Map4k4 in exosomes decreased inflammatory reaction, blood lipid, plaque area, MMP-9 expression and increased α-SMA expression, as well as inhibited apoptosis index of AS mice. CONCLUSION: Functional studies revealed that exosomal miR-125b-5p from BMSCs suppresses atherosclerotic plaque formation via inhibiting Map4k4 expression.


Assuntos
Medula Óssea/metabolismo , Exossomos/metabolismo , Regulação da Expressão Gênica , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/genética , Placa Aterosclerótica/prevenção & controle , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Exossomos/genética , Masculino , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Placa Aterosclerótica/etiologia , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia
3.
Mol Med Rep ; 23(5)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33649864

RESUMO

Atherosclerosis (AS) is a chronic inflammatory disease of the vascular wall with multiple causes. AS is the primary pathological basis of cardiovascular disease and stroke. Moreover, carotid plaque rupture and thrombus formation are the main causes of ischemic stroke. Therefore, understanding the formation of carotid plaques may help improve the prediction and prevention of cardiovascular and cerebrovascular events. Endothelial cell dysfunction results in re­endothelialization and angiogenesis in atherosclerotic plaques, thus promoting plaque destabilization. The aim of the present study was to evaluate the effect of circular RNA (circRNA) molecules in serum exosomes (serum­Exos) from patients with stable plaque atherosclerosis (SA) and unstable/vulnerable plaque atherosclerosis (UA). Specifically, the effect of circRNA on human umbilical vein endothelial cell (HUVEC) behavior and the mechanisms underlying plaque destabilization in AS were evaluated. Serum­Exos were isolated, then identified using transmission electron microscopy, nanoparticle tracking analysis and western blotting. The serum­Exo­circRNA expression profile of patients with SA or UA was investigated using a circRNA array. The relationship between circRNA­006896 in serum­Exos and biochemical parameters of patients with SA and UA were analyzed using Spearman's correlation. In addition, HUVECs were incubated with serum­Exos for in vitro functional assays. The present study demonstrated that circRNAs expression profiles in SA and UA serum­Exos were significantly different, indicating a potential role for circRNAs in carotid plaque destabilization. The expression of circRNA­0006896 was positively correlated with triglyceride, low­density lipoprotein cholesterol (LDL­C) and C­reactive protein levels, and negatively correlated with albumin levels in patients with UA. However, circRNA­0006896 expression was positively correlated with LDL­C in patients with SA. Using bioinformatic analysis, a competing endogenous RNA (ceRNA) network was selected to study the regulatory roles of circRNA­0006896 in serum­Exos. Additionally, in HUVECs treated with serum­Exos derived from patients with UA, the expression of circRNA­0006896 in HUVECs was upregulated. This was accompanied by decreased expression of microRNA­1264 and SOCS3, increased levels of DNMT1 and phosphorylated STAT3. HUVEC proliferation and migration were significantly increased in the UA group, compared with the mock and SA groups. This finding indicates that the circRNA­0006896­miR-1264­DNMT1 axis plays an important role in carotid plaque destabilization by regulating the behavior of endothelial cells. Moreover, it suggests that circRNA­0006896 may represent a therapeutic target for controlling JNK/STAT3 signaling in HUVECs. Thus, this study may provide insight on potential interventions against vulnerable plaque formation in patients with AS.


Assuntos
Aterosclerose/genética , Artérias Carótidas/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/genética , Células Endoteliais/metabolismo , MicroRNAs/genética , Placa Aterosclerótica/genética , RNA Circular/genética , Adulto , Aterosclerose/metabolismo , Artérias Carótidas/patologia , Movimento Celular/genética , Proliferação de Células/genética , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Exossomos/genética , Exossomos/metabolismo , Exossomos/ultraestrutura , Feminino , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Placa Aterosclerótica/metabolismo , Transdução de Sinais/genética
4.
Nat Metab ; 3(2): 166-181, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33619382

RESUMO

Stable atherosclerotic plaques are characterized by a thick, extracellular matrix-rich fibrous cap populated by protective ACTA2+ myofibroblast (MF)-like cells, assumed to be almost exclusively derived from smooth muscle cells (SMCs). Herein, we show that in murine and human lesions, 20% to 40% of ACTA2+ fibrous cap cells, respectively, are derived from non-SMC sources, including endothelial cells (ECs) or macrophages that have undergone an endothelial-to-mesenchymal transition (EndoMT) or a macrophage-to-mesenchymal transition (MMT). In addition, we show that SMC-specific knockout of the Pdgfrb gene, which encodes platelet-derived growth factor receptor beta (PDGFRß), in Apoe-/- mice fed a Western diet for 18 weeks resulted in brachiocephalic artery lesions nearly devoid of SMCs but with no changes in lesion size, remodelling or indices of stability, including the percentage of ACTA2+ fibrous cap cells. However, prolonged Western diet feeding of SMC Pdgfrb-knockout mice resulted in reduced indices of stability, indicating that EndoMT- and MMT-derived MFs cannot compensate indefinitely for loss of SMC-derived MFs. Using single-cell and bulk RNA-sequencing analyses of the brachiocephalic artery region and in vitro models, we provide evidence that SMC-to-MF transitions are induced by PDGF and transforming growth factor-ß and dependent on aerobic glycolysis, while EndoMT is induced by interleukin-1ß and transforming growth factor-ß. Together, we provide evidence that the ACTA2+ fibrous cap originates from a tapestry of cell types, which transition to an MF-like state through distinct signalling pathways that are either dependent on or associated with extensive metabolic reprogramming.


Assuntos
Metabolismo Energético/genética , Placa Aterosclerótica/patologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Actinas/metabolismo , Animais , Apolipoproteínas E/genética , Artéria Braquial/patologia , Dieta Ocidental , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Transição Epitelial-Mesenquimal , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos de Músculo Liso/patologia , Placa Aterosclerótica/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo
5.
Int J Mol Sci ; 22(3)2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33540814

RESUMO

Vascular smooth muscle cells (VSMCs) provide vital contractile force within blood vessel walls, yet can also propagate cardiovascular pathologies through proliferative and pro-inflammatory activities. Such phenotypes are driven, in part, by the diverse effects of long non-coding RNAs (lncRNAs) on gene expression. However, lncRNA characterisation in VSMCs in pathological states is hampered by incomplete lncRNA representation in reference annotation. We aimed to improve lncRNA representation in such contexts by assembling non-reference transcripts in RNA sequencing datasets describing VSMCs stimulated in vitro with cytokines, growth factors, or mechanical stress, as well as those isolated from atherosclerotic plaques. All transcripts were then subjected to a rigorous lncRNA prediction pipeline. We substantially improved coverage of lncRNAs responding to pro-mitogenic stimuli, with non-reference lncRNAs contributing 21-32% for each dataset. We also demonstrate non-reference lncRNAs were biased towards enriched expression within VSMCs, and transcription from enhancer sites, suggesting particular relevance to VSMC processes, and the regulation of neighbouring protein-coding genes. Both VSMC-enriched and enhancer-transcribed lncRNAs were large components of lncRNAs responding to pathological stimuli, yet without novel transcript discovery 33-46% of these lncRNAs would remain hidden. Our comprehensive VSMC lncRNA repertoire allows proper prioritisation of candidates for characterisation and exemplifies a strategy to broaden our knowledge of lncRNA across a range of disease states.


Assuntos
Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/metabolismo , Placa Aterosclerótica/metabolismo , RNA Longo não Codificante/análise , Aorta/citologia , Vasos Coronários/citologia , Citocinas/farmacologia , Conjuntos de Dados como Assunto , Elementos Facilitadores Genéticos , Perfilação da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , RNA Longo não Codificante/isolamento & purificação , RNA-Seq , Estresse Mecânico , Transcrição Genética/efeitos dos fármacos , Transcriptoma
6.
Arterioscler Thromb Vasc Biol ; 41(3): 1218-1228, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33472398

RESUMO

OBJECTIVE: COMP (cartilage oligomeric matrix protein) is abundantly expressed in the cardiovascular system, cartilage, and atherosclerotic plaques. We investigated if the total COMP (COMPtotal) and COMP neoepitope (COMPneo) with other cardiovascular markers and clinical parameters could identify symptomatic carotid stenosis. Approach and Results: Blood samples were collected from patients with symptomatic carotid stenosis (stenosis, n=50), patients with stroke without carotid stenosis but small plaques (plaque, n=50), and control subjects (n=50). COMPtotal and COMPneo were measured using an ELISA. Ninety-two cardiovascular disease markers were measured by the Olink CVD kit. The presence of native COMP and COMPneo was determined by immunohistochemistry. The concentration of COMPneo was higher and COMPtotal was lower in the stenosis group. When the concentration was compared between the stenosis and control groups, IL-1ra (interleukin-1 receptor antagonist protein), IL6 (interleukin-6), REN (Renin), MMP1 (matrix metalloproteinase-1), TRAIL-R2 (tumor necrosis factor-related apoptosis-inducing ligand receptor 2), ITGB1BP2 (integrin beta 1 binding protein 2), and COMPneo were predictive of stenosis. Conversely, KLK6 (kallikrein-6), COMPtotal, NEMO (nuclear factor-kappa-B essential modulator), SRC (Proto-oncogene tyrosine-protein kinase Src), SIRT2 (SIR2-like protein), CD40 (cluster of differentiation 40), TF (tissue factor), MP (myoglobin), and RAGE (receptor for advanced glycation end-products) were predictive of the control group. Model reproducibility was good with the receiver operating characteristic plot area under the curve being 0.86. When comparing the plaque group and stenosis group, COMPneo, GAL (galanin), and PTX3 (pentraxin-related protein PTX3) were predictive of stenosis. Model reproducibility was excellent (receiver operating characteristic plot area under the curve 0.92). COMPneo was detected in smooth muscle-, endothelial-, and foam-cells in carotid stenosis. CONCLUSIONS: Degradation of COMP may be associated with atherosclerosis progression and generation of a specific COMP fragment-COMPneo. This may represent a novel biomarker that together with COMPtotal and other risk-markers could be used to identify symptomatic carotid stenosis. Graphic Abstract: A graphic abstract is available for this article.


Assuntos
Estenose das Carótidas/sangue , Proteína de Matriz Oligomérica de Cartilagem/sangue , Proteína de Matriz Oligomérica de Cartilagem/imunologia , Epitopos/sangue , Idoso , Biomarcadores/sangue , Biomarcadores/metabolismo , Estenose das Carótidas/imunologia , Proteína de Matriz Oligomérica de Cartilagem/metabolismo , Estudos de Casos e Controles , Progressão da Doença , Epitopos/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Cardiovasculares , Placa Aterosclerótica/sangue , Placa Aterosclerótica/imunologia , Placa Aterosclerótica/metabolismo , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/imunologia
7.
Arterioscler Thromb Vasc Biol ; 41(3): 1062-1075, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33472399

RESUMO

OBJECTIVE: Plaque necrosis is a key feature of defective resolution in atherosclerosis. Recent evidence suggests that necroptosis promotes plaque necrosis; therefore, we sought to determine how necroptotic cells (NCs) impact resolution programs in plaques. Approach and Results: To investigate the role(s) of necroptosis in advanced atherosclerosis, we used mice deficient of Mlkl, an effector of necroptosis. Mlkl-/- mice that were injected with a gain-of-function mutant PCSK9 (AAV8-gof-PCSK9) and fed a Western diet for 16 weeks, showed significantly less plaque necrosis, increased fibrous caps and improved efferocytosis compared with AAV8-gof-PCSK9 injected wt controls. Additionally, hypercholesterolemic Mlkl-/- mice had a significant increase in proresolving mediators including resolvin D1 (RvD1) and a decrease in prostanoids including thromboxane in plaques and in vitro. We found that exuberant thromboxane released by NCs impaired the clearance of both apoptotic cells and NCs through disruption of oxidative phosphorylation in macrophages. Moreover, we found that NCs did not readily synthesize RvD1 and that exogenous administration of RvD1 to macrophages rescued NC-induced defective efferocytosis. RvD1 also enhanced the uptake of NCs via the activation of p-AMPK (AMP-activated protein kinase), increased fatty acid oxidation, and enhanced oxidative phosphorylation in macrophages. CONCLUSIONS: These results suggest that NCs derange resolution by limiting key SPMs and impairing the efferocytic repertoire of macrophages. Moreover, these findings provide a molecular mechanism for RvD1 in directing proresolving metabolic programs in macrophages and further suggests RvD1 as a potential therapeutic strategy to limit NCs in tissues. Graphic Abstract: A graphic abstract is available for this article.


Assuntos
Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Graxos/metabolismo , Macrófagos/metabolismo , Necroptose/fisiologia , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apoptose , Feminino , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Necrose , Fosforilação Oxidativa , Fagocitose , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Prostaglandinas/metabolismo , Proteínas Quinases/deficiência , Proteínas Quinases/genética
8.
Arterioscler Thromb Vasc Biol ; 41(3): 1076-1091, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33504177

RESUMO

OBJECTIVE: Chondroitin sulfate proteoglycans are the primary constituents of the macrophage glycosaminoglycan and extracellular microenvironment. To examine their potential role in atherogenesis, we investigated the biological importance of one of the chondroitin sulfate glycosaminoglycan biosynthesis gene, ChGn-2 (chondroitin sulfate N-acetylgalactosaminyltransferase-2), in macrophage foam cell formation. Approach and Results: ChGn-2-deficient mice showed decreased and shortened glycosaminoglycans. ChGn-2-/-/LDLr-/- (low-density lipoprotein receptor) mice generated less atherosclerotic plaque after being fed with Western diet despite exhibiting a metabolic phenotype similar to that of the ChGn-2+/+/LDLr-/- littermates. We demonstrated that in macrophages, ChGn-2 expression was upregulated in the presence of oxLDL (oxidized LDL), and glycosaminoglycan was substantially increased. Foam cell formation was significantly altered by ChGn-2 in both mouse peritoneal macrophages and the RAW264.7 macrophage cell line. Mechanistically, ChGn-2 enhanced oxLDL binding on the cell surface, and as a consequence, CD36-an important macrophage membrane scavenger receptor-was differentially regulated. CONCLUSIONS: ChGn-2 alteration on macrophages conceivably influences LDL accumulation and subsequently accelerates plaque formation. These results collectively suggest that ChGn-2 is a novel therapeutic target amenable to clinical translation in the future. Graphic Abstract: A graphic abstract is available for this article.


Assuntos
Aterosclerose/metabolismo , Células Espumosas/metabolismo , Glicosaminoglicanos/metabolismo , N-Acetilgalactosaminiltransferases/metabolismo , Animais , Aterosclerose/etiologia , Aterosclerose/patologia , Modelos Animais de Doenças , Feminino , Células Espumosas/patologia , Glicosaminoglicanos/química , Lipoproteínas LDL/metabolismo , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , N-Acetilgalactosaminiltransferases/deficiência , N-Acetilgalactosaminiltransferases/genética , Placa Aterosclerótica/etiologia , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Células RAW 264.7 , Regulação para Cima
9.
Exp Mol Pathol ; 118: 104604, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33434610

RESUMO

INTRODUCTION AND AIMS: Oxytocin (OT) is a neuropeptide hormone secreted by the posterior pituitary gland. Deficits in OT action have been observed in patients with behavioral and mood disorders, some of which correlate with an increased risk of cardiovascular disease (CVD). Recent research has revealed a wider systemic role that OT plays in inflammatory modulation and development of atherosclerotic plaques. This study investigated the role that OT plays in cholesterol transport and foam cell formation in LPS-stimulated THP-1 human macrophages. METHODS: THP-1 differentiated macrophages were treated with media, LPS (100 ng/ml), LPS + OT (10 pM), or LPS + OT (100 pM). Changes in gene expression and protein levels of cholesterol transporters were analyzed by real time quantitative PCR (RT-qPCR) and Western blot, while oxLDL uptake and cholesterol efflux capacity were evaluated with fluorometric assays. RESULTS: RT-qPCR analysis revealed a significant increase in ABCG1 gene expression upon OT + LPS treatment, compared to LPS alone (p = 0.0081), with Western blotting supporting the increase in expression of the ABCG1 protein. Analysis of oxLDL uptake showed a significantly lower fluorescent value in LPS + OT (100pM) -treated cells when compared to LPS alone (p < 0.0001). While not statistically significant (p = 0.06), cholesterol efflux capacity increased with LPS + OT treatment. CONCLUSION: We demonstrate here that OT can attenuate LPS-mediated lipid accumulation in THP-1 macrophages. These findings support the hypothesis that OT could be used to reduce pro-inflammatory and potentially atherogenic changes observed in patients with heightened CVD risk. This study suggests further exploration of OT effects on monocyte and macrophage cholesterol handling in vivo.


Assuntos
Aterosclerose/tratamento farmacológico , Colesterol/metabolismo , Células Espumosas/efeitos dos fármacos , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Ocitocina/farmacologia , Placa Aterosclerótica/tratamento farmacológico , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Aterosclerose/induzido quimicamente , Aterosclerose/metabolismo , Aterosclerose/patologia , Células Cultivadas , Células Espumosas/metabolismo , Células Espumosas/patologia , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Macrófagos/metabolismo , Macrófagos/patologia , Ocitócicos/farmacologia , Placa Aterosclerótica/induzido quimicamente , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Receptores de Ocitocina/metabolismo
10.
Molecules ; 26(2)2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33419179

RESUMO

A new conjugate of gallato zirconium (IV) phthalocyanine complexes (PcZrGallate) has been obtained from alkilamino-modified SiO2 nanocarriers (SiO2-(CH2)3-NH2NPs), which may potentially be used in photodynamic therapy of atherosclerosis. Its structure and morphology have been investigated. The photochemical properties of the composite material has been characterized. in saline environments when exposed to different light sources Reactive oxygen species (ROS) generation in DMSO suspension under near IR irradiation was evaluated. The PcZrGallate-SiO2 conjugate has been found to induce a cytotoxic effect on macrophages after IR irradiation, which did not correspond to ROS production. It was found that SiO2 as a carrier helps the photosensitizer to enter into the macrophages, a type of cells that play a key role in the development of atheroma. These properties of the novel conjugate may make it useful in the photodynamic therapy of coronary artery disease.


Assuntos
Complexos de Coordenação , Portadores de Fármacos , Indóis , Fotoquimioterapia , Fármacos Fotossensibilizantes , Placa Aterosclerótica , Dióxido de Silício , Zircônio , Animais , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Indóis/química , Indóis/farmacologia , Camundongos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Placa Aterosclerótica/tratamento farmacológico , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Células RAW 264.7 , Dióxido de Silício/química , Dióxido de Silício/farmacologia , Zircônio/química , Zircônio/farmacologia
11.
Phytomedicine ; 81: 153430, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33341451

RESUMO

BACKGROUND: Atherosclerosis is a chronic vascular disease and characterized by accumulation within the intima of inflammatory cells, smooth muscle cells, lipid, and connective tissue. PURPOSE: The purpose of the present study was to identify natural agents that commonly reverse advanced atherosclerotic plaque to early atherosclerotic plaque. METHODS: Differentially expressed genes (DEGs) were analyzed in silico. The differentially expressed genes from 9 intimal thickening and 8 fibrous cap atheroma tissue which were collected from GEO data were assessed by the connectivity map. Natural candidate securinine, a main compound from Securinega suffruticosa, was selected and administrated 1, 5 mg/kg/day in apolipoprotein-E-deficient (ApoE KO) mice for 18 weeks. RESULTS: Securinine significantly showed lowered blood pressure and improvement of metabolic parameters with hyperlipidemia. The impairment in vasorelaxation was remarkably decreased by treatment with securinine. H&E staining revealed that treatment with securinine reduced atherosclerotic lesions. Securinine suppressed the expression of adhesion molecules and matrix metalloproteinase-2/-9 in both ApoE KO and vascular endothelial cells (HUVEC). In HUVEC pretreatment with securinine significantly inhibited ROS generation and NF-κB activation. Growth curve assays using the real-time cell analyzer showed that securinine significantly decreased TNF-α-induced aortic smooth muscle cell proliferation and migration in a dose-dependent manner. CONCLUSION: Securinine may be a potential natural candidate for the treatment of atherosclerosis because it attenuates vascular inflammation and dysfunction as well as vascular lesion.


Assuntos
Aterosclerose/tratamento farmacológico , Azepinas/farmacologia , Endotélio Vascular/efeitos dos fármacos , Compostos Heterocíclicos de Anel em Ponte/farmacologia , Lactonas/farmacologia , Piperidinas/farmacologia , Substâncias Protetoras/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Aterosclerose/metabolismo , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Knockout para ApoE , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , NF-kappa B/metabolismo , Placa Aterosclerótica/tratamento farmacológico , Placa Aterosclerótica/metabolismo , Vasodilatação/efeitos dos fármacos
12.
Int J Mol Sci ; 21(24)2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33339419

RESUMO

There is an intensive effort to identify biomarkers to predict cardiovascular disease evolution. We aimed to determine the potential of microRNAs to predict the appearance of cardiovascular events (CVEs) in patients with peripheral artery disease (PAD) following femoral artery bypass surgery. Forty-seven PAD patients were enrolled and divided into two groups, without CVEs (n = 35) and with CVEs (n = 12), during 1 year follow-up. Intra-surgery atherosclerotic plaques from femoral arteries were collected and the levels of miR-142, miR-223, miR-155, and miR-92a of the primary transcripts of these microRNAs (pri-miRNAs), and gene expression of Drosha and Dicer were determined. Results showed that, in the plaques, miR-142, miR-223, and miR-155 expression levels were significantly increased in PAD patients with CVEs compared to those without CVEs. Positive correlations between these miRNAs and their pri-miRNAs levels and the Dicer/Drosha expression were observed. In the plasma of PAD patients with CVEs compared to those without CVEs, miR-223 and miR-142 were significantly increased. The multiple linear regression analyses revealed significant associations among several plasma lipids, oxidative and inflammatory parameters, and plasma miRNAs levels. Receiver operator characteristic (ROC) analysis disclosed that plasma miR-142 levels could be an independent predictor for CVEs in PAD patients. Functional bioinformatics analyses supported the role of these miRNAs in the regulation of biological processes associated with atherosclerosis. Taken together, these data suggest that plasma levels of miR-142, miR-223, miR-155, and miR-92a can significantly predict CVEs among PAD patients with good accuracy, and that plasma levels of miR-142 can be an independent biomarker to predict post-surgery CVEs development in PAD patients.


Assuntos
MicroRNAs/sangue , Doença Arterial Periférica/sangue , Placa Aterosclerótica/sangue , Complicações Pós-Operatórias/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Biomarcadores/metabolismo , Feminino , Artéria Femoral/cirurgia , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Doença Arterial Periférica/metabolismo , Doença Arterial Periférica/cirurgia , Placa Aterosclerótica/metabolismo , Complicações Pós-Operatórias/metabolismo , Enxerto Vascular/efeitos adversos
13.
Int J Mol Sci ; 21(24)2020 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-33317170

RESUMO

Carotid atherosclerotic plaque rupture can lead to cerebrovascular accident (CVA). By comparing RNA-Seq data from vascular smooth muscle cells (VSMC) extracted from carotid atheroma surgically excised from a group of asymptomatic and symptomatic subjects, we identified more than 700 genomic variants associated with symptomatology (p < 0.05). From these, twelve single nucleotide polymorphisms (SNPs) were selected for further validation. Comparing genotypes of a hospital-based cohort of asymptomatic with symptomatic patients, an exonic SNP in the BIRC6 (BRUCE/Apollon) gene, rs35286811, emerged as significantly associated with CVA symptomatology (p = 0.002; OR = 2.24). Moreover, BIRC6 mRNA levels were significantly higher in symptomatic than asymptomatic subjects upon measurement by qPCR in excised carotid atherosclerotic tissue (p < 0.0001), and significantly higher in carriers of the rs35286811 risk allele (p < 0.0001). rs35286811 is a proxy of a GWAS SNP reported to be associated with red cell distribution width (RDW); RDW was increased in symptomatic patients (p < 0.03), but was not influenced by the rs35286811 genotype in our cohort. BIRC6 is a negative regulator of both apoptosis and autophagy. This work introduces BIRC6 as a novel genetic risk factor for stroke, and identifies autophagy as a genetically regulated mechanism of carotid plaque vulnerability.


Assuntos
Artérias Carótidas/metabolismo , Proteínas Inibidoras de Apoptose/genética , Placa Aterosclerótica/genética , Polimorfismo de Nucleotídeo Único , Artérias Carótidas/patologia , Humanos , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia
14.
Life Sci ; 257: 117658, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32621921

RESUMO

BACKGROUND: Curcumin (Cur) is a hydrophobic polyphenol compound derived from the rhizome of the herb Curcuma longa. Cur has a wide spectrum of biological and pharmacological activities. It has been shown that human cytomegalovirus (HCMV) infection was an important risk factor for atherosclerosis (AS) and Cur exhibited an outstanding anti-HCMV effect. However, anti-AS effects of Cur remain unclear when HCMV infected endothelial cells. AIMS: This study will investigate the anti-AS activities and mechanism of Cur,when HCMV infected in vivo and in vitro. MATERIALS AND METHODS: Cur (0.5, 1, and 2 µM) was used to explore the anti-AS activities and mechanism after HCMV infected endothelial cells in vitro. ApoE-/- mice were fed a high fat and cholesterol diet (HD) and given 4000,000 copies/mouse MCMV infection by intraperitoneal and treated with ganciclovir (5 mg/kg/d), Cur (25, 15 mg/kg/d) for 10 weeks in vivo. KEY FINDINGS: As our results showed that Cur inhibited CMV replication and proliferation, reduced the intracellular ROS overproduction, decreased the release of inflammatory cytokines, down-regulated the level of HMGB1-TLRS-NF-κB signaling pathway-related proteins in vitro experiments. Cur reduced the serum levels of LDL-C, TC and TG, significantly decreased the formation of atherosclerotic plaque in the aorta, reduced the lipid deposition in liver and inflammatory damage in heart, lung and kidney in vivo experiments. SIGNIFICANCE: This study showed that Cur prevent AS progression by inhibiting CMV activity and CMV-induced HMGB1-TLRS-NF-κB signaling pathway.


Assuntos
Aterosclerose/tratamento farmacológico , Curcumina/farmacologia , Citomegalovirus/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerose/metabolismo , Curcuma/metabolismo , Curcumina/metabolismo , Citocinas/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Camundongos Transgênicos , NF-kappa B/metabolismo , Extratos Vegetais/farmacologia , Placa Aterosclerótica/metabolismo , Transdução de Sinais/efeitos dos fármacos
15.
Proc Natl Acad Sci U S A ; 117(27): 15818-15826, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32541024

RESUMO

Atherosclerosis is the process underlying heart attack and stroke. Despite decades of research, its pathogenesis remains unclear. Dogma suggests that atherosclerotic plaques expand primarily via the accumulation of cholesterol and inflammatory cells. However, recent evidence suggests that a substantial portion of the plaque may arise from a subset of "dedifferentiated" vascular smooth muscle cells (SMCs) which proliferate in a clonal fashion. Herein we use multicolor lineage-tracing models to confirm that the mature SMC can give rise to a hyperproliferative cell which appears to promote inflammation via elaboration of complement-dependent anaphylatoxins. Despite being extensively opsonized with prophagocytic complement fragments, we find that this cell also escapes immune surveillance by neighboring macrophages, thereby exacerbating its relative survival advantage. Mechanistic studies indicate this phenomenon results from a generalized opsonin-sensing defect acquired by macrophages during polarization. This defect coincides with the noncanonical up-regulation of so-called don't eat me molecules on inflamed phagocytes, which reduces their capacity for programmed cell removal (PrCR). Knockdown or knockout of the key antiphagocytic molecule CD47 restores the ability of macrophages to sense and clear opsonized targets in vitro, allowing for potent and targeted suppression of clonal SMC expansion in the plaque in vivo. Because integrated clinical and genomic analyses indicate that similar pathways are active in humans with cardiovascular disease, these studies suggest that the clonally expanding SMC may represent a translational target for treating atherosclerosis.


Assuntos
Aterosclerose/metabolismo , Clonagem Molecular , Ativação do Complemento , Miócitos de Músculo Liso/metabolismo , Fagocitose/fisiologia , Animais , Antígeno CD47/metabolismo , Linhagem da Célula , Proliferação de Células , Complemento C3/genética , Complemento C3/metabolismo , Feminino , Humanos , Inflamação , Macrófagos/metabolismo , Masculino , Camundongos Knockout para ApoE , Miócitos de Músculo Liso/citologia , Placa Aterosclerótica/metabolismo , Análise de Sequência de RNA , Regulação para Cima
16.
Arterioscler Thromb Vasc Biol ; 40(6): e166-e179, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32349534

RESUMO

OBJECTIVE: Recent studies suggest that the P2Y12 (P2Y purinoceptor 12) receptor of vascular smooth muscle cells in atherosclerotic plaques aggravates atherosclerosis, and P2Y12 receptor inhibitors such as CDL (clopidogrel) may effectively treat atherosclerosis. It is imperative to identify an effective biomarker for reflecting the P2Y12 receptor expression on vascular smooth muscle cells in plaques. Approach and Results: We found that there was a positive correlation between the level of circulating sLRP1 (soluble low-density lipoprotein receptor-related protein 1) and the number of LRP1+ α-SMA+ (α-smooth muscle actin), P2Y12+, or P2Y12+ LRP1+ cells in plaques from apoE-/- mice fed a high-fat diet. Furthermore, activation of the P2Y12 receptor increased the expression and shedding of LRP1 in vascular smooth muscle cells by inhibiting cAMP (3'-5'-cyclic adenosine monophosphate)/PKA (protein kinase A)/SREBP-2 (sterol regulatory element binding transcription factor 2). Conversely, genetic knockdown or pharmacological inhibition of the P2Y12 receptor had the opposite effects. Additionally, CDL decreased the number of lesional LRP1+ α-SMA+ cells and the levels of circulating sLRP1 by activating cAMP/PKA/SREBP-2 in apoE-/- mice fed a high-fat diet. CONCLUSIONS: Our study suggests that sLRP1 may be a biomarker that reflects the P2Y12 receptor level in plaques and has the potential to be an indicator for administering P2Y12 receptor inhibitors for patients with atherosclerosis.


Assuntos
Biomarcadores/análise , Expressão Gênica , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/análise , Placa Aterosclerótica/metabolismo , Receptores Purinérgicos P2Y12/genética , Actinas/análise , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Apolipoproteínas E/fisiologia , Clopidogrel/farmacologia , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Dieta Hiperlipídica , Técnicas de Silenciamento de Genes , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/química , Músculo Liso Vascular/metabolismo , Placa Aterosclerótica/química , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Receptores Purinérgicos P2Y12/efeitos dos fármacos , Receptores Purinérgicos P2Y12/fisiologia , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo
17.
Metabolism ; 107: 154231, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32298723

RESUMO

BACKGROUND: The mechanism of pyruvate kinase M2 (PKM2)-mediated inflammatory signalling in macrophages when plaques rupture and the impact of hyperglycaemia on the signalling are unclear. The present study aimed to explore the impact of hyperglycaemia on PKM2-mediated NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome/stress granule signalling in macrophages and its correlation with plaque vulnerability in vivo and in vitro. METHODS: From July to December 2019, 80 patients with coronary heart disease (CHD) were divided into acute ST-segment elevation myocardial infarction (STEMI) (n = 57) (DM-STEMI, n = 21; non-DM-STEMI, n = 36) and stable CHD (SCHD) groups (n = 23). Circulating mononuclear cells were isolated. The value of peak troponin I (TnI), the Global Registry of Acute Coronary Events (GRACE) risk score, and the expression levels of the related markers were quantified and compared. In vitro studies on the THP-1 cells were also performed. RESULTS: The DM-STEMI group had a higher value of peak TnI and a higher GRACE risk score than the non-DM-STEMI group (p < 0.05). The highest expression levels of PKM2, NLRP3, interleukin (IL)-1ß, and IL-18 and the lowest expression level of GTPase activating protein (SH3 domain)-binding protein 1 (G3BP1) (a stress granule marker protein) were observed in the DM-STEMI group, and they were followed by the non-DM-STEMI group and the SCHD group (p < 0.05). In vitro studies showed similar results and that TEPP-46 (a PKM2 activator) and 2-deoxy-d-glucose (a toxic glucose analogue) reversed the hyperglycaemia-induced increase in the NLRP3 inflammasome and decrease in G3BP1 expression. CONCLUSION: Hyperglycaemia might increase the activation of PKM2-mediated NLRP3 inflammasome/stress granule signalling and increase plaque vulnerability, associating it with worse prognosis. PKM2 may be a novel prognostic indicator and a new target for the treatment of patients with CHD and DM.


Assuntos
Proteínas de Transporte/metabolismo , Grânulos Citoplasmáticos , Hiperglicemia/fisiopatologia , Inflamassomos , Macrófagos/metabolismo , Proteínas de Membrana/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Placa Aterosclerótica/metabolismo , Hormônios Tireóideos/metabolismo , Idoso , Linhagem Celular , Doença das Coronárias/metabolismo , DNA Helicases/sangue , Feminino , Humanos , Hiperglicemia/induzido quimicamente , Interleucinas/sangue , Masculino , Pessoa de Meia-Idade , Proteínas de Ligação a Poli-ADP-Ribose/sangue , RNA Helicases/sangue , Proteínas com Motivo de Reconhecimento de RNA/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/metabolismo , Troponina I/metabolismo
18.
Sci Rep ; 10(1): 6127, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32273567

RESUMO

It has been suggested that miR-144 is pro-atherosclerotic via effects on reverse cholesterol transportation targeting the ATP binding cassette protein. This study used proteomic analysis to identify additional cardiovascular targets of miR-144, and subsequently examined the role of a newly identified regulator of atherosclerotic burden in miR-144 knockout mice receiving a high fat diet. To identify affected secretory proteins, miR-144 treated endothelial cell culture medium was subjected to proteomic analysis including two-dimensional gel separation, trypsin digestion, and nanospray liquid chromatography coupled to tandem mass spectrometry. We identified 5 gel spots representing 19 proteins that changed consistently across the biological replicates. One of these spots, was identified as vimentin. Atherosclerosis was induced in miR-144 knockout mice by high fat diet and vascular lesions were quantified by Oil Red-O staining of the serial sectioned aortic root and from en-face views of the aortic tree. Unexpectedly, high fat diet induced extensive atherosclerosis in miR-144 knockout mice and was accompanied by severe fatty liver disease compared with wild type littermates. Vimentin levels were reduced by miR-144 and increased by antagomiR-144 in cultured cardiac endothelial cells. Compared with wild type, ablation of the miR-144/451 cluster increased plasma vimentin, while vimentin levels were decreased in control mice injected with synthetic miR-144. Furthermore, increased vimentin expression was prominent in the commissural regions of the aortic root which are highly susceptible to atherosclerotic plaque formation. We conclude that miR-144 maybe a potential regulator of the development of atherosclerosis via changes in vimentin signaling.


Assuntos
MicroRNAs/genética , Placa Aterosclerótica/metabolismo , Vimentina/genética , Animais , Células Cultivadas , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Placa Aterosclerótica/genética , Vimentina/metabolismo
19.
J Pharmacol Exp Ther ; 373(3): 463-475, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32238453

RESUMO

Leonurine (LEO) is a bioactive small molecular compound that has protective effects on the cardiovascular system and prevents the early progression of atherosclerosis; however, it is not clear whether LEO is effective for plaque stability. A novel mouse atherosclerosis model involving tandem stenosis (TS) of the right carotid artery combined with western diet (WD) feeding was used. Apolipoprotein E gene-deficient mice were fed with a WD and received LEO administration daily for 13 weeks. TS was introduced 6 weeks after the onset of experiments. We found that LEO enhanced plaque stability by increasing fibrous cap thickness and collagen content while decreasing the population of CD68-positive cells. Enhanced plaque stability by LEO was associated with the nitric oxide synthase (NOS)-nitric oxide (NO) system. LEO restored the balance between endothelial NOS(E)- and inducible NOS(iNOS)-derived NO production; suppressed the NF-κB signaling pathway; reduced the level of the inflammatory infiltration in plaque, including cytokine interleukin 6; and downregulated the expression of adhesion molecules. These findings support the distinct role of LEO in plaque stabilization. In vitro studies with oxidized low-density lipoprotein-challenged human umbilical vein endothelial cells revealed that LEO balanced NO production and inhibited NF-κB/P65 nuclear translocation, thus mitigating inflammation. In conclusion, the restored balance of the NOS-NO system and mitigated inflammation contribute to the plaque-stabilizing effect of LEO. SIGNIFICANCE STATEMENT: LEO restored the balance between endothelial NOS and inducible NOS in NO production and inhibited excessive inflammation in atherosclerotic "unstable" and rupture-prone plaques in apolipoprotein E gene-deficient mice. The protective effect of LEO for stabilizing atherosclerotic plaques was due to improved collagen content, increased fibrous cap thickness, and decreased accumulation of macrophages/foam cells. So far, LEO has passed the safety and feasibility test of phase I clinical trial.


Assuntos
Aterosclerose/tratamento farmacológico , Ácido Gálico/análogos & derivados , Inflamação/tratamento farmacológico , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico/metabolismo , Placa Aterosclerótica/tratamento farmacológico , Animais , Aterosclerose/metabolismo , Linhagem Celular , Ácido Gálico/farmacologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Placa Aterosclerótica/metabolismo , Transdução de Sinais/efeitos dos fármacos
20.
J Pharmacol Sci ; 143(2): 106-111, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32173266

RESUMO

Varenicline is a widely used and effective drug for smoking cessation. We have previously reported experimental evidence suggesting that varenicline increases the risk of cardiovascular events. Varenicline progresses atherosclerotic plaque formation in apolipoprotein E knockout (ApoE KO) mice. This adverse effect is likely due to enhanced net uptake of oxidized low-density lipoprotein (oxLDL) in macrophages as a result of increased scavenger receptors and decreased cholesterol efflux transporters. However, a regimen has not yet been presented for avoidance or amelioration of the risk for varenicline-induced cardiovascular events. The aim of this study was to examine the effect of hesperidin, a citrus flavonoid, on varenicline-aggravated atherosclerotic plaque formation in apolipoprotein E knockout (ApoE KO) mice. Hesperidin inhibited the aggravating effect of varenicline in the whole aorta, aortic arch, and aortic root of ApoE KO mice. In addition, hesperidin protected against varenicline-enhanced oxLDL net uptake by blocking the increased expression of CD36 and LOX-1 scavenger receptors and decreased expression of ABCA1 and ABCG1 cholesterol efflux transporters in RAW 264.7 cells. Our findings suggest that hesperidin can avoid or ameliorate the risk for cardiovascular events induced by varenicline treatment.


Assuntos
Apolipoproteínas E , Regulação para Baixo/efeitos dos fármacos , Hesperidina/farmacologia , Lipoproteínas LDL/metabolismo , Macrófagos/metabolismo , Placa Aterosclerótica/metabolismo , Vareniclina/efeitos adversos , Vareniclina/antagonistas & inibidores , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Antígenos CD36/metabolismo , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/prevenção & controle , Camundongos , Camundongos Knockout , Células RAW 264.7 , Receptores Depuradores Classe E/metabolismo
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