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1.
Life Sci ; 241: 117144, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31830482

RESUMO

BACKGROUND: As an inflammation-related cytokine, interleukin (IL)-5 has been reported to be involved in the development of cardiovascular diseases, such as chronic heart failure and atherosclerosis. However, the role of IL-5 in acute aortic dissection (AAD) has barely been explored. METHODS: Aortic tissue samples from normal donors and patients with AAD were collected, and the expression and localization of IL-5 in aortic tissue were analyzed. In addition, a mouse AAD model was established by administering angiotensin II (Ang II) to ß-aminopropionitrile (BAPN)-treated mice. Morphological examinations and histopathologic analyses were performed to evaluate the effects of IL-5 overexpression on the occurrence of AAD. RESULTS: IL-5 expression was significantly decreased in aorta samples from AAD patients compared to those from donors, and macrophages were the main source of IL-5. In addition, IL-5 expression was decreased in plasma and aortic tissue samples from AAD mice. IL-5 overexpression markedly attenuated the occurrence of AAD in mice and produced corresponding decreases in the inflammatory response and cell apoptosis. In cocultures of macrophages and smooth muscle cells (SMCs), IL-5 overexpression in the macrophages significantly reduced Ang II-induced SMC apoptosis. CONCLUSION: IL-5 overexpression suppresses the development of AAD by reducing inflammation and SMC apoptosis. These results suggest that IL-5 is a potential therapeutic target in AAD.


Assuntos
Aneurisma Dissecante/prevenção & controle , Apoptose , Modelos Animais de Doenças , Inflamação/prevenção & controle , Interleucina-5/metabolismo , Macrófagos/patologia , Miócitos de Músculo Liso/patologia , Aminopropionitrilo/toxicidade , Aneurisma Dissecante/induzido quimicamente , Aneurisma Dissecante/complicações , Aneurisma Dissecante/metabolismo , Angiotensina II/toxicidade , Animais , Aorta/metabolismo , Aorta/patologia , Estudos de Casos e Controles , Feminino , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Interleucina-5/genética , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Miócitos de Músculo Liso/metabolismo , Prognóstico
2.
J Photochem Photobiol B ; 202: 111666, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31837585

RESUMO

In this study, the effect of Polyp-Au-GO nanocomposite on VSMC proliferation, cell cycle proteins, down-regulation of mRNA in the rat was tested. Briefly, Polyp-Au-GO composite material was synthesized and characterized by UV-Vis spectra, X-ray diffraction (XRD), Raman spectroscopy, Fourier transform infrared spectroscopy (FT-IR), Scanning electron microscopy (SEM) and Transmission electron microscopy (TEM). Polyp-Au-GO composite exhibited the absorbance peak at 530 nm. XRD analysis confirmed the crystalline particle with size ranging between 16.5 and 32.6 nm. The crystallinity differences of the nanocomposite were examined by Raman spectroscopy analysis. The presence of a strong band (1500 cm-1) and the absence of other lower frequency bands confirmed that the absence of crystallinity of Polyp-Au-GO nanocomposite. The thermal properties of Polyp-Au-GO nanocomposite were determined by TGA analysis. The results revealed that 15% of its weight loss has occurred at 300 °C. Further, the growth of VSMCs was inhibited by the treatment of Polyp-Au-GO composite at 72 h. The IC50 value was registered at 0.57 µg/mL. Additionally, the Polyp-Au-GO composite arrest G1 cell cycle and down-regulated cell cycle proteins. These Polyp-Au-GO composite also reduced the extracellular ERK1/2 phosphorylation. Furthermore, Polyp-Au-GO composite inhibited TNF-R-evoked inflammatory responses. Moreover, Polyp-Au-GO composite inhibited of CEC proliferation. These results suggest that Polyp-Au-GO composite inhibits VSMC proliferation and TNF-R-mediated inflammatory responses. This study suggested the therapeutic role of Polyp-Au-GO composite in cardiovascular disease.


Assuntos
Grafite/química , Nanocompostos/química , Polifenóis/química , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Nanocompostos/toxicidade , Tamanho da Partícula , Fosforilação/efeitos dos fármacos , Polifenóis/farmacologia , Ratos
3.
Gene ; 725: 144143, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31629816

RESUMO

Atherosclerosis is a common cardiovascular disorder and is characterized by damage of endothelial cells, cell inflammation, hyper-proliferation of vascular smooth muscle cells and the accumulation of extracellular lipids and fibrous tissues. In this study, we firstly examined the expression level of long intergenic non-protein coding RNA, regulator of reprogramming (linc-ROR) in homocysteine (Hcy)-stimulated human aortic smooth muscle cells (HASMCs), and then looked into the potential molecular signaling axis of linc-ROR in regulating the proliferation and migration of HASMCs. Hcy promoted HASMC proliferation and up-regulated linc-ROR expression. Functional studies showed that linc-ROR exerted enhanced actions on the proliferation and migration of HASMCs. In addition, linc-ROR acted as a competing endogenous RNA for miR-195-5p and repressed the miR-195-5p expression in HASMCs. Linc-ROR was up-regulated the miR-195-3p was down-regulated in the plasma from CAD patients when compared to normal controls. Furthermore, fibroblast growth factor 2 (FGF2) was identified as a target of miR-195-5p and was negatively regulated by miR-195-5p in HASMCs. The rescue experiments revealed that linc-ROR-mediated HASMC proliferation and migration may be via regulating miR-195-5p/FGF2 axis. Linc-ROR inhibition blocked the miR-195-5p/FGF2 signaling in Hcy-treated HASMCs, and this effect may also involve in the miR-195-5p/FGF2 axis. To summarize, the data of the present study identified the up-regulation of linc-ROR in Hcy-stimulated HASMCs, and further mechanistic functional studies revealed that linc-ROR promoted HASMC proliferation and migration via regulating miR-195-5p/FGF2 axis. The present study provided the novel actions of linc-ROR in regulating HASMC proliferation and migration, which may be related to the pathophysiology of atherosclerosis.


Assuntos
Fator 2 de Crescimento de Fibroblastos/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Aorta/citologia , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Autofagia/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Fator 2 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/fisiologia , Homocisteína/farmacologia , Humanos , MicroRNAs/genética , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , RNA Longo não Codificante/biossíntese , RNA Longo não Codificante/genética , Transdução de Sinais
4.
DNA Cell Biol ; 38(12): 1470-1479, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31633376

RESUMO

Vascular smooth muscle cells (VSMCs) of ascending aorta and TBX18+ sinus node both originated from the second heart field. The study explored whether ascending aortic smooth muscle cells in vitro could be reprogrammed into pacemaker-like cells with human TBX18. In the study, VSMCs were infected with TBX18, and then cocultured with neonatal rat ventricular cardiomyocytes (NRVMs) in vitro. By overexpressing TBX18, the transfected VSMCs expressed high levels of hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4), insulin gene enhancer binding protein 1, and human dwarf homeobox gene SHOX2, cardiac troponin I, and low level of connexin 43. In addition, funny current (If) was recorded by patch clamp appeared the time and voltage dependence in TBX18 group, which the amplitude of If density was from -5.164 ± 0.662 pA/pF to -0.765 ± 0.358 pA/pF (n = 14). Furthermore, TBX18-transfected VSMCs coupled with NRVMs showed typical action potential of pacemaker-like cells and the beating rate was faster (178.00 ± 7.55 bpm, p < 0.05) compared with other groups. In conclusion, our study indicated that transcription factor TBX18 could reprogram VSMCs into pacemaker-like cells in vitro.


Assuntos
Aorta/citologia , Reprogramação Celular , Músculo Liso Vascular/citologia , Miócitos Cardíacos/citologia , Marca-Passo Artificial , Proteínas com Domínio T/metabolismo , Animais , Animais Recém-Nascidos , Aorta/metabolismo , Diferenciação Celular , Células Cultivadas , Masculino , Músculo Liso Vascular/metabolismo , Miócitos Cardíacos/metabolismo , Ratos , Ratos Sprague-Dawley
5.
J Agric Food Chem ; 67(46): 12752-12760, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31642668

RESUMO

Atherosclerosis, the major risk of cardiovascular events, is a chronic vascular inflammatory disease. Pterostilbene is a naturally occurring dimethylated analogue of resveratrol and has recently been demonstrated to be beneficial against cardiovascular diseases. However, the underlying mechanisms of pterostilbene on atherosclerosis remain elusive. Experimental atherosclerosis was induced by a high-fat diet (HFD) in apolipoprotein E knockout (ApoE-/-) mice. Pterostilbene was administered intragastrically for 16 weeks. We found that pterostilbene significantly attenuated thoracic and abdominal atherosclerotic plaque formation in HFD-fed ApoE-/-mice, accompanied by modulated lipid profiles and reduced production of proinflammatory cytokines (including IL-6, IFN-γ, and TNF-α). In addition, pterostilbene restored vascular redox balance in thoracic and abdominal aorta, evidenced by enhanced catalase (CAT) expression and activities, and decreased malondialdehyde and H2O2 production. Notably, pterostilbene specifically induced CAT expression and activities in the vascular smooth muscle cells (VSMCs) of thoracic and abdominal aorta. In vitro, pterostilbene markedly promoted the expression and activity of CAT and decreased ox-low-density lipoprotein (LDL)-mediated VSMC proliferation and intracellular H2O2 production, which was abolished by CAT siRNA knockdown or inhibition. Pterostilbene-induced CAT expression was associated with inhibition of Akt, PRAS40, and GSK-3ß signaling activation and upregulation of PTEN. Our data clearly demonstrated that pterostilbene exerted an antiatherosclerotic effect by inducing CAT and modulating the VSMC function.


Assuntos
Aterosclerose/tratamento farmacológico , Catalase/metabolismo , Músculo Liso Vascular/enzimologia , Estilbenos/administração & dosagem , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerose/genética , Aterosclerose/metabolismo , Catalase/genética , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Lipoproteínas LDL/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/metabolismo , Oxirredução
6.
Nat Genet ; 51(11): 1580-1587, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31659325

RESUMO

Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P < 5.0 × 10-8). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein-deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification.


Assuntos
Aterosclerose/patologia , Predisposição Genética para Doença , Histona Desacetilases/metabolismo , Histona Desacetilases/fisiologia , Contração Muscular , Músculo Liso Vascular/patologia , Proteínas Repressoras/metabolismo , Proteínas Repressoras/fisiologia , Calcificação Vascular/patologia , Idoso , Animais , Aorta/metabolismo , Aorta/patologia , Aterosclerose/genética , Aterosclerose/metabolismo , Estudos de Coortes , Feminino , Proteínas Ativadoras de GTPase/genética , Proteínas Ativadoras de GTPase/metabolismo , Estudo de Associação Genômica Ampla , Histona Desacetilases/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Músculo Liso Vascular/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único , Proteínas Repressoras/genética , Calcificação Vascular/genética , Calcificação Vascular/metabolismo
7.
Life Sci ; 237: 116896, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31605707

RESUMO

AIMS: Population-based studies have shown that exercise has anti-atherosclerotic effects, but the mechanisms underlying this cardiac protection are poorly understood. The aim of this study was to investigate if the anti-atherosclerotic effects of exercise are associated with changes in neuropeptide Y (NPY) expression in apolipoprotein E-deficient (ApoE-/-) mice. MAIN METHODS: Thirty-one male ApoE-/- mice were randomly divided into regular exercise (5 days/week), occasional exercise (1-2 days/week), and sedentary groups. After 8 weeks, atherosclerotic burden and plaque stability were measured by histological and morphological analysis. Quantitative real-time PCR and immunohistochemistry were used to measure the expression of NPY and its receptors in the aorta. KEY FINDINGS: Eight weeks of occasional exercise was equally effective as regular exercise at preventing atherosclerotic plaque formation and enhancing atherosclerotic plaque stability. This was shown by increased plaque collagen and smooth muscle cell content and decreased plaque lipid and macrophage content. The expression of NPY and its receptors in the vasculature was decreased in the regular exercise and occasional exercise groups, and this expression was significantly correlated with the progress of atherosclerosis. Moreover, exercise may reduce the activity of macrophages by down-regulating the expression of NPY Y1 receptors, thereby reducing the release of inflammatory cytokines. SIGNIFICANCE: These results suggest that exercise training can attenuate plaque burden and enhance atherosclerotic plaque stability. The anti-atherosclerotic effect of exercise appears to be, at least in part, dependent on down-regulation of the expression of NPY and its receptors (especially Y1 receptors) in the aorta.


Assuntos
Apolipoproteínas E/fisiologia , Aterosclerose/prevenção & controle , Regulação da Expressão Gênica , Inflamação/prevenção & controle , Neuropeptídeo Y/metabolismo , Condicionamento Físico Animal , Animais , Aorta/metabolismo , Aorta/patologia , Aterosclerose/etiologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Neuropeptídeo Y/genética
8.
Chem Biol Interact ; 314: 108842, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31586451

RESUMO

BACKGROUND AND AIMS: Chronic psychosocial stress is a risk factor for cardiovascular disease. In view of the important role of dipeptidyl peptidase-4 (DPP-4) in human pathophysiology, we studied the role of DPP-4 in stress-related vascular aging in mice, focusing on oxidative stress and the inflammatory response. METHODS AND RESULTS: Male mice were randomly divided into a non-stress group and an immobilization stress group treated for 2 weeks. Chronic stress accelerates aortic senescence and increases plasma DPP-4 levels. Stress increased the levels of gp91phox, p22phox, p47phox, p67phox, p53, p27, p21, p16INK4A, vascular cell adhesion molecule-1, intracellular adhesion molecule-1, monocyte chemoattractant protein-1, matrix metalloproteinase-2 (MMP-2), MMP-9, cathepsin S (Cat S), and Cat K mRNAs and/or protein in the aorta of the stressed mice and decreased their levels of endothelial nitric oxide synthase and SirTuin1 (SirT1). DPP-4 inhibitors can improve stress-induced targeting molecules and morphological changes. In vitro, the inhibition of DPP-4 also alleviated the changes in the oxidative and inflammatory molecules in response to hydrogen peroxide in human umbilical vein endothelial cells. CONCLUSIONS: DPP-4 inhibition can improve vascular aging in stressed mice, possibly by improving oxidative stress production and vascular inflammation. Our results suggest that DPP-4 may become a new therapeutic target for chronic stress-related vascular aging in metabolic cardiovascular diseases.


Assuntos
Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Aorta/metabolismo , Aorta/patologia , Dipeptidil Peptidase 4/sangue , Dipeptidil Peptidase 4/química , Regulação para Baixo/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Peróxido de Hidrogênio/metabolismo , Inflamação/patologia , Inflamação/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase/metabolismo , Pirimidinas/farmacologia , Sirtuína 1/metabolismo , Estresse Fisiológico
9.
Toxicol Lett ; 316: 27-34, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31513887

RESUMO

OBJECTIVE: Atherosclerosis is an autoimmune inflammatory disease that is closely associated with long-term exposure to fine particulate matter (PM2.5). CD4+CD25+Foxp3+ regulatory T cells (Tregs) play a critical role in the regulation of T cell-mediated immune responses, and the depletion of CD4+CD25+Foxp3+ Tregs has been thought to play a prominent role in atherosclerosis. Therefore, we investigated the association between the CD4+CD25+Foxp3+ Tregs population and atherosclerotic development in ApoE-/- mice exposed to PM2.5. METHODS: We employed a real-world system to subject 40 ApoE-/- mice to ambient inhalation of PM2.5 (PM2.5 group, n = 20) or filtered air (FA group, n = 20) for 12 weeks. PM2.5 source apportionment, atherosclerotic lesions within aorta, lipid deposition and plaque accumulation in whole artery, serum level of inflammatory factors and lipid profiles, CD4+CD25+Foxp3+ Tregs population in splenocytes, Foxp3 protein and mRNA expressions in descending aorta and spleen were quantified, respectively. RESULTS: The daily average concentration of PM2.5 was 57.4 ± 25.6 µg/m3. Atherosclerotic lesions within aorta, lipid deposition and plaque accumulation in whole artery, serum levels of IL-6, TNF-α, TC and LDL-C in the PM2.5 group increased significantly compared to the FA group. Whereas, serum levels of IL-10 and TGF-ß, CD4+CD25+Foxp3+ Tregs population in splenocytes, Foxp3 protein and mRNA expressions in descending aorta and spleen in the PM2.5 group decreased significantly compared to the FA group. CONCLUSION: These results suggest that PM2.5 could accelerate the development of atherosclerosis in ApoE-/- mice, which is related to CD4+CD25+Foxp3+ Tregs down-regulation, as well as lipid deposition and systemic inflammation.


Assuntos
Aorta/efeitos dos fármacos , Doenças da Aorta/induzido quimicamente , Aterosclerose/induzido quimicamente , Fatores de Transcrição Forkhead/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Material Particulado/toxicidade , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Aorta/imunologia , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/sangue , Doenças da Aorta/imunologia , Doenças da Aorta/patologia , Aterosclerose/sangue , Aterosclerose/imunologia , Aterosclerose/patologia , Biomarcadores/sangue , LDL-Colesterol/sangue , Citocinas/sangue , Modelos Animais de Doenças , Progressão da Doença , Fatores de Transcrição Forkhead/imunologia , Predisposição Genética para Doença , Mediadores da Inflamação/sangue , Subunidade alfa de Receptor de Interleucina-2/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Tamanho da Partícula , Fenótipo , Placa Aterosclerótica , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Fatores de Tempo
10.
Oxid Med Cell Longev ; 2019: 6721531, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396305

RESUMO

Aims: The neutrophil recruiting cytokine Interleukin-17A (IL-17A) is a key component in vascular dysfunction and arterial hypertension. Moreover, IL-17A has a central role for the vascular infiltration of myeloid cells into the arterial wall in Angiotensin II-induced vascular inflammation. The intention of our study was to analyze the impact of T cell-derived IL-17A on hypertension, vascular function, and inflammation. Methods and Results: Chronic IL-17A overexpression in T cells (CD4-IL-17Aind/+ mice) resulted in elevated reactive oxygen species in the peripheral blood and a significant vascular dysfunction compared to control mice. The vascular dysfunction seen in the CD4-IL-17Aind/+ mice was only accompanied by a modest and nonsignificant accumulation of inflammatory cells within the vessel wall. Therefore, infiltrating myeloid cells did not serve as an explanation of the vascular dysfunction seen in a chronic IL-17A-driven mouse model. In addition to vascular dysfunction, CD4-IL-17Aind/+ mice displayed vascular fibrosis with highly proliferative fibroblasts. This fibroblast proliferation was induced by exposure to IL-17A as confirmed by in vitro experiments with primary murine fibroblastic cells. We also found that the ·NO/cGMP pathway was downregulated in the vasculature of the CD4-IL-17Aind/+ mice, while levels of protein tyrosine kinase 2 (PYK2), an oxidative stress-triggered process associated with T cell activation, were upregulated in the perivascular fat tissue (PVAT). Conclusions: Our data demonstrate that T cell-derived IL-17A elicits vascular dysfunction by mediating proliferation of fibroblasts and subsequent vascular fibrosis associated with PYK2 upregulation.


Assuntos
GMP Cíclico/metabolismo , Endotélio Vascular/fisiopatologia , Interleucina-17/metabolismo , Óxido Nítrico/metabolismo , Linfócitos T/metabolismo , Animais , Aorta/metabolismo , Aorta/patologia , Proliferação de Células , Regulação para Baixo , Fibroblastos/citologia , Fibroblastos/metabolismo , Fibrose , Quinase 2 de Adesão Focal/metabolismo , Interleucina-17/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Subunidades Proteicas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Guanilil Ciclase Solúvel/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Regulação para Cima
11.
Mol Cell Biochem ; 462(1-2): 61-73, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31446617

RESUMO

Atherosclerosis plays an important role in the pathology of coronary heart disease, cerebrovascular disease, and systemic vascular disease. Long non-coding RNAs (lncRNAs) are involved in most biological processes and are deregulated in many human diseases. However, the expression alteration and precise role of lncRNAs during atherosclerosis are unknown. We report here the systematic profiling of lncRNAs and mRNAs in an ApoE-deficient (ApoE-/-) mouse model of atherosclerosis. Clariom D solutions for the mouse Affymetrix Gene Chip were employed to analyze the RNAs from control and ApoE-/- mice. The functions of the differentially expressed mRNAs and lncRNAs and the relationships of their expression with atherosclerosis were analyzed by gene ontology, co-expression network, pathway enrichment, and lncRNA target pathway network analyses. Quantitative real-time PCR (QRT-PCR) was used to determine the expression of mRNAs and lncRNAs. A total of 2212 differentially expressed lncRNAs were identified in ApoE-/- mice, including 1186 up-regulated and 1026 down-regulated lncRNAs (|FC| ≥ 1.1, p < 0.05). A total of 1190 differentially expressed mRNAs were found in the ApoE-/- mice with 384 up-regulated and 806 down-regulated (|FC| ≥ 1.1, p < 0.05). Bioinformatics analyses demonstrated extensive co-expression of lncRNAs and mRNAs and concomitant deregulation of multiple signaling pathways associated with the initiation and progression of atherosclerosis. The identified differentially expressed mRNAs and lncRNAs as well as the related signaling pathways may provide systematic information for understanding the pathogenesis and identifying biomarkers for the diagnosis, treatment, and prognosis of atherosclerosis.


Assuntos
Apolipoproteínas E/deficiência , Aterosclerose/genética , Perfilação da Expressão Gênica , RNA Longo não Codificante/genética , Animais , Aorta/metabolismo , Aorta/patologia , Apolipoproteínas E/metabolismo , Análise por Conglomerados , Ontologia Genética , Redes Reguladoras de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
12.
Mediators Inflamm ; 2019: 8691294, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31427887

RESUMO

Background: Interleukin- (IL-) 18 is a proinflammatory cytokine related to cardiovascular diseases, including hypertension and atherosclerosis. This study is aimed at determining whether IL-18 is related to aortic dissection (AD) and identifying the underlying mechanisms. Methods: IL-18 expression in human aorta samples from AD (n = 8) and non-AD (NAD, n = 7) patients was measured. In addition, the IL-18, IL-6, interferon- (IFN-) γ, and IL-18-binding protein (IL-18BP) concentrations in plasma samples collected from the NAD and AD patients were detected. The effects of IL-18 on macrophage differentiation and smooth muscle cell (SMC) apoptosis were investigated in vitro. Results: IL-18 expression was significantly increased in the aorta samples from the AD patients compared with those from the NAD patients, especially in the torn section. Aortic IL-18 was mainly derived from macrophages and also partly derived from CD4+ T lymphocytes and vascular SMCs. Plasma IL-18, IFN-γ, and IL-6 levels were significantly higher in the AD group than in the NAD group, and the IL-18 levels were positively correlated with the IFN-γ and IL-6 levels. In addition, plasma IL-18BP and free IL-18 levels were also elevated in the AD group. Linear regression analysis showed that the IL-18 level was independently associated with the presence of AD. In addition, anti-mouse IL-18-neutralizing monoclonal antibodies (anti-IL-18 nAb) inhibited angiotensin II-induced M1 macrophage differentiation and SMC apoptosis in vitro. Conclusion: IL-18 may participate in AD by regulating macrophage differentiation and macrophage-induced SMC apoptosis.


Assuntos
Aorta/metabolismo , Interleucina-18/sangue , Interleucina-18/metabolismo , Aneurisma Dissecante , Apoptose/fisiologia , Diferenciação Celular/fisiologia , Humanos , Macrófagos/metabolismo
13.
Mediators Inflamm ; 2019: 6710759, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379468

RESUMO

Epidemiological studies have demonstrated that cardiovascular diseases (CVDs) are the leading cause of death in the world. Atherosclerosis, a kind of chronic vascular disorder related to multiple pathogenic processes, has been reported to be an underlying cause of CVDs. Shexiang Baoxin Pill (SBP) is a traditional Chinese medicine formulation and has been broadly used for the treatment of CVDs in East Asia. However, whether SBP affects the development of atherosclerosis is poorly understood. The aim of this study was to investigate the antiatherosclerotic roles and relevant mechanisms of SBP in apolipoprotein E knockout mice. Our results showed that SBP treatment markedly decreased the size of atherosclerotic plaques of the entire aorta and the aortic sinus. Biochemical analyses indicated that SBP gavage improved oxidative stress in vivo, as seen by the level elevation of SOD, CAT, and GSH and the level reduction of MDA, H2O2, and MPO. Moreover, the concentration of MCP-1, IFN-γ, and IL-17A was reduced, and the content of IL-10 and TGF-ß1 was increased in the serum from SBP-treated mice. We discovered that the expression levels of inflammatory factors including VCAM-1, ICAM-1, IL-6, and IL-2 in the vascular wall of the SBP group were also decreased in comparison with those of the normal saline group. Moreover, we found that SBP alleviated the activation of inflammation-related pathways in the aorta tissue, as seen by the level elevation of Mfn2 and reduced phosphorylation of p38, JNK, and NF-κB. Furthermore, western blot showed that SBP administration reduced the level of SR-A and LOX-1 and elevated the content of LXRα, ABCA1, and ABCG1 in the arterial wall, indicating that SBP was capable of alleviating lipid influx and facilitating lipid efflux. In conclusion, our data suggested that SBP exerted antiatherosclerotic effects via improving inflammation response and inhibiting lipid accumulation.


Assuntos
Aorta/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , Transportador 1 de Cassete de Ligação de ATP/sangue , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/sangue , Animais , Aorta/efeitos dos fármacos , Apolipoproteínas E/sangue , Aterosclerose/sangue , Doenças Cardiovasculares/sangue , Inflamação , Molécula 1 de Adesão Intercelular/sangue , Interleucina-2/sangue , Interleucina-6/sangue , Camundongos , Camundongos Knockout , Estresse Oxidativo/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/sangue
14.
J Physiol Pharmacol ; 70(2)2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31443091

RESUMO

The proliferation of vascular smooth muscle cells plays a crucial role in pathogenesis of cardiovascular disease. The principal objective of this study was to determine the effects of Ojeoksan (OJS) on human aortic smooth muscle cell (HASMC) proliferation induced by tumor necrosis factor α (TNF-aα). Thymidine incorporation after TNF-α treatment was increased and this effect was inhibited significantly by OJS treatment. HASMC proliferation and migration by kinetic live cell imaging were also reduced by treatment with OJS. TNF-α induced the expression of cyclins/cyclin-dependent kinases (CDKs) and reduced the expression of p21waf1/cip1/p27kip1. However, OJS also attenuated the expression of TNF-α-induced cell-cycle regulatory proteins. The results of Western blot analysis demonstrated that the TNF-α treated HASMC secreted gelatinases, probably including MMP-2/-9, which may be involved in the invasion and migration of HASMC. Additionally, OJS suppressed the mRNA expression levels of matrix metalloproteinase-2/-9 (MMP-2/-9) in a dose-dependent manner. OJS inhibited the production of TNF-α-induced hydrogen peroxide (H2O2) and the formation of DCF-sensitive intracellular reactive oxygen species (ROS). Further, OJS suppressed the nuclear translocation and phosphorylation of inhibitor of kappa B-α (IκB-α) of nuclear factor κB (NF-κB) under TNF-α conditions. Our results demonstrate that OJS exerts inhibitory effects on TNF-α-induced HASMC proliferation and migration, suggesting the involvement of the inhibition of both MMP-2 and MMP-9 expressions, and the downregulation of ROS/NF-κB signaling. Thus, herbal decoction OJS may be a possible therapeutic approach to the inhibition of cardiovascular disease including atherosclerosis.


Assuntos
Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Aorta/efeitos dos fármacos , Aorta/metabolismo , Células Cultivadas , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Regulação para Baixo/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/farmacologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
15.
Kidney Blood Press Res ; 44(4): 823-834, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31266041

RESUMO

BACKGROUND/AIMS: Vascular calcification is common and progressive in chronic kidney disease, including kidney transplant recipients (KTRs). However, the risk factors associated with the progression of aortic calcification (AoC) in KTRs have not been fully elucidated. In the present study, we evaluated AoC and examined the factors associated with its advancement in KTRs. MATERIALS: This was a prospective longitudinal study that included 98 KTRs. We quantitatively investigated infrarenal abdominal AoC using the Agatston score, as measured by multi-slice computed tomography. After the baseline investigation, a follow-up scan was performed after 3 years, and the Agatston scores were obtained again. The changes in laboratory data affecting the 2nd Agatston scores were examined by multivariable analysis using non-linear regression after adjustment for several confounders. RESULTS: The 2nd Agatston scores were significantly greater than the baseline Agatston scores (p < 0.001). After adjustment for the confounders, the change in corrected serum calcium exhibited a significant non-linear correlation with the 2nd Agatston scores (p = 0.022 for non-linearity/p = 0.031 for the effect of corrected serum calcium). Moreover, an interaction was present from the baseline AoC in the effect of corrected serum calcium on the progression of AoC, and the effect of hypercalcemia was greater in patients with higher baseline Agatston scores (p = 0.049). CONCLUSION: The present study revealed that hypercalcemia is a risk factor for the development of infrarenal abdominal AoC in KTRs. Furthermore, the effect of hypercalcemia was greater in patients with more severe vascular calcification.


Assuntos
Aorta/patologia , Progressão da Doença , Hipercalcemia/complicações , Transplante de Rim/efeitos adversos , Calcificação Vascular/etiologia , Adulto , Aorta/metabolismo , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Rigidez Vascular
16.
Biol Pharm Bull ; 42(9): 1464-1470, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31270287

RESUMO

Aortic dissection (AD) diseases are characterized by degeneration of the aortic media. Oxidative stress plays a crucial role in the development of AD. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1 (NOX1) deficiency reduces the incidence of aortic dissection induced by angiotensin II, but its mechanism remains to be further elucidated. The expression of Fibulin-5 is decreased in patients with AD, but its upstream mechanism is still unclear. This study was to clarify the relationship between NOX1 and Fibulin-5 in the AD. Results showed that the expressions of NOX1 and Fibulin-5 were increased and decreased in the AD, respectively. Next, by employing gain- and loss-of-function approaches in vitro, NOX1 negatively regulated Fibulin-5 in the vascular smooth muscle cells. Moreover, the blunted activity of NOX1 with VAS2870 could upregulate the expression of Fibulin-5. These findings indicate NOX1 is a negative modulator of Fibulin-5 in the AD.


Assuntos
Aneurisma Dissecante/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Miócitos de Músculo Liso/metabolismo , NADPH Oxidase 1/metabolismo , Aneurisma Dissecante/genética , Animais , Aorta/metabolismo , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Músculo Liso Vascular/citologia , NADPH Oxidase 1/genética
17.
Hum Exp Toxicol ; 38(10): 1212-1223, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31256681

RESUMO

High fructose corn syrup (HFCS) has been shown to cause cardiovascular toxicity via oxidative stress and inflammation. The aim of this study is to demonstrate the protective effects of melatonin (MLT) against HFCS-induced endothelial and cardiac dysfunction via oxidative stress and inflammation. Thirty-two Sprague Dawley male rats were distributed into three groups as control, HFCS, and HFCS + MLT. HFCS form F55 was prepared as 20% fructose syrup solution and given to the rats through drinking water for 10 weeks, and MLT administrated 10 mg/kg/day orally for last 6 weeks in addition to F55. After decapitation, blood and half of the heart samples were collected for biochemical analysis and other half of the tissues for histopathological and immunohistochemical analysis. Aspartate transaminase, creatine kinase MB, lactate dehydrogenase, total oxidant status and oxidative stress index, and caspase-3 levels increased and total antioxidant status levels decreased significantly in HFCS group. MLT treatment reversed all these parameters. Histopathologically, hyperemia, endothelial cell damage and increased levels of angiogenin, C-reactive protein, inducible nitric oxide synthase, myeloperoxidase and decreased sirtuin-1 (SIRT-1) expressions were observed in HFCS group. MLT ameliorated all these changes. MLT has an anti-inflammatory, antioxidant, antiapoptotic effects on HFCS-induced cardiovascular toxicity through enhancing the expression of SIRT-1.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Xarope de Milho Rico em Frutose/toxicidade , Melatonina/farmacologia , Miocárdio/metabolismo , Substâncias Protetoras/farmacologia , Sirtuína 1/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Biomarcadores/metabolismo , Cardiotoxicidade , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/prevenção & controle , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Coração/efeitos dos fármacos , Masculino , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Transdução de Sinais
18.
J Physiol Pharmacol ; 70(2)2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31356180

RESUMO

We have recently demonstrated the antithrombotic effect of eplerenone on the arterial thrombotic process in diabetic rats associated with suppression of coagulation and enhancement of fibrinolysis. The aim of this study was to evaluate the role of platelets and endothelium in the mechanism of eplerenone antithrombotic action. Diabetes was induced in male Wistar rats with a single injection of streptozotocin (65 mg/kg). On the 25th day, treatment with eplerenone (100 mg/kg) was initiated for 10 days. Eplerenone did not change hemodynamic parameters (blood pressure, carotid blood flow, and heart rate), however, improved endothelium-dependent vasorelaxation in aortas and small mesenteric arteries, enhanced the aortic amounts of mRNA of endothelial nitric oxide synthase (eNOS), and reduced mRNA of nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase 2. A prolongation of bleeding time and decrease in platelet adhesion to collagen ex vivo was also observed. These changes were accompanied by prolonged time to occlusion and increased blood flow, and finally reduced thrombus mass in diabetic rats. The inhibition of NOS with L-NAME reduced the eplerenone antithrombotic effect. Our study provides evidence that the antithrombotic effect of eplerenone in diabetic rats is nitric oxide-dependent and associated with inhibiting the adhesion of platelets, as well as normalizing endothelial function. The mechanism of eplerenone antithrombotic action in diabetes is a result of improved endothelial nitric oxide bioavailability that leads to the improvement vascular and platelet function.


Assuntos
Plaquetas/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Eplerenona/farmacologia , Fibrinolíticos/farmacologia , Óxido Nítrico/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Plaquetas/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Endotélio Vascular/metabolismo , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos , Ratos Wistar , Estreptozocina/farmacologia , Vasodilatação/efeitos dos fármacos
19.
Amyloid ; 26(3): 148-155, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31210552

RESUMO

Objective: To explore the relationship of aortic medial amyloid with biochemical and micromechanical properties of the aortic wall in aneurysm patients. Methods: Human aortic tissues removed during aneurysm surgery from tricuspid (idiopathic degenerative aneurysm, DA) and bicuspid valve (BAV) patients were subjected to oscillatory nanoindentation experiments to determine localised mechanical properties of the tissue (shear storage modulus, G´ and shear loss modulus, G˝). Collagen, elastin, matrix metalloproteinase 2 and glycosaminoglycans concentrations were determined, along with relative levels of aortic medial amyloid-related factors (medin, milk fat globule-EGF factor 8, oligomers and fibrils). Measurements were combined with clinical data and statistical analyses performed. Results: The DA cohort can be divided based on their phenotype. One group shared similar characteristics with BAV patients, termed bicuspid like phenotype-tricuspid valve. The second group had high amyloid oligomer species present with a significantly lower G´ (p = .01), indicative of reduced elastic response of the tissue, termed amyloid-rich. Conclusions: We identified a group of DA patients with high amyloid oligomers and altered micromechanical and structural properties of the vessel wall. We propose these findings as a cause for aneurysm formation in these patients. Amyloid is not found in BAV patients, suggesting at least two distinct mechanisms for pathogenesis.


Assuntos
Aorta/metabolismo , Aneurisma da Aorta Torácica/diagnóstico , Aneurisma da Aorta Torácica/metabolismo , Valva Mitral/metabolismo , Valva Tricúspide/metabolismo , Idoso , Antígenos de Superfície/genética , Antígenos de Superfície/metabolismo , Aorta/patologia , Aorta/cirurgia , Aneurisma da Aorta Torácica/patologia , Aneurisma da Aorta Torácica/cirurgia , Biomarcadores/metabolismo , Fenômenos Biomecânicos , Estudos de Coortes , Colágeno/genética , Colágeno/metabolismo , Elastina/genética , Elastina/metabolismo , Feminino , Expressão Gênica , Glicosaminoglicanos/metabolismo , Humanos , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Pessoa de Meia-Idade , Proteínas do Leite/genética , Proteínas do Leite/metabolismo , Valva Mitral/patologia , Valva Mitral/cirurgia , Fenótipo , Resistência ao Cisalhamento , Valva Tricúspide/patologia , Valva Tricúspide/cirurgia
20.
Medicine (Baltimore) ; 98(24): e16013, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31192949

RESUMO

BACKGROUND: Aortic dissection (AD) is one of the most lethal cardiovascular diseases. The aim of this study was to identify core genes and pathways revealing pathogenesis in AD. METHODS: We screened differentially expressed mRNAs and miRNAs using mRNA and miRNA expression profile data of AD from Gene Expression Omnibus. Then functional and pathway enrichment analyses of differential expression genes (DEGs) was performed utilizing the database for annotation, visualization, and integrated discovery (DAVID). Target genes with differential expression miRNAs (DEMIs) were predicted using the miRWalk database, and the intersection between these predictions and DEGs was selected as differentially expressed miRNA-target genes. In addition, a protein-protein interaction (PPI) network and miRNA-mRNA regulatory network were constructed. RESULTS: In total, 130 DEGs and 47 DEMIs were identified from mRNA and miRNA microarray, respectively, and 45 DEGs were DEMI-target genes. The PPI and miRNA-mRNA network included 79 node genes and 74 node genes, respectively, while 23 hub genes and 2 hub miRNAs were identified. The DEGs, PPI and modules differential expression miRNA-target genes were all mainly enriched in cell cycle, cell proliferation and cell apoptosis signaling pathways. CONCLUSION: Taken above, the study reveals some candidate genes and pathways potentially involving molecular mechanisms of AD. These findings provide a new insight for research and treatment of AD.


Assuntos
Aneurisma Dissecante/metabolismo , MicroRNAs/metabolismo , RNA Mensageiro/metabolismo , Aneurisma Dissecante/genética , Aorta/metabolismo , Biologia Computacional , Expressão Gênica , Redes Reguladoras de Genes , Humanos
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