Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.760
Filtrar
1.
Life Sci ; 237: 116919, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610200

RESUMO

AIMS: Stroke-prone spontaneously hypertensive rats (SHRSP) show significantly lower body weight than normotensive Wistar-Kyoto rats (WKY). Our hypotheses are as follows: weight loss of the skeletal muscle is related to hypertension-related diseases, and muscle hypotrophy is useful as a therapeutic target for hypertension and hypertension-related diseases. In this study, we aimed to investigate the pathophysiological characteristics of muscle hypotrophy in SHRSP to determine the therapeutic target molecule(s). MAIN METHODS: The difference in skeletal muscles in the lower leg between WKY and SHRSP was evaluated mainly through weight/tibial length, histological, gene expression, and protein expression analyses. KEY FINDINGS: SHRSP had a significantly lower weight/tibial length in soleus and gastrocnemius, but not in plantaris and tibialis anterior, indicating that muscles consisting of a relatively high amount of slow muscle fiber were affected. This result was confirmed by the histological analysis of soleus, showing that type I fiber mainly decreased the fiber size. Microarray and protein expression analyses showed that the muscle-specific ubiquitin ligase, muscle RING finger 1 (MuRF1), but not atrogin-1, was highly expressed in soleus, but not in plantaris, in SHRSP. TNF-like weak inducer of apoptosis receptor (TWEAKR) was predicted as a MuRF1 up-regulator by Ingenuity Pathway Analysis and immunostained only in type II fiber in WKY but in both type I and II fibers in SHRSP. SIGNIFICANCE: TWEAKR is a type II-specific receptor in the skeletal muscle. Ectopic TWEAKR expression in type I fiber of SHRSP is most likely involved in slow muscle-specific hypotrophy through MuRF1 overexpression.


Assuntos
Hipertensão/patologia , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/patologia , Músculo Liso Vascular/patologia , Atrofia Muscular/patologia , Acidente Vascular Cerebral/patologia , Receptor de TWEAK/metabolismo , Animais , Hipertensão/complicações , Hipertensão/metabolismo , Masculino , Fibras Musculares Esqueléticas/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Músculo Liso Vascular/metabolismo , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Receptor de TWEAK/genética , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
2.
Presse Med ; 48(9): 919-930, 2019 Sep.
Artigo em Francês | MEDLINE | ID: mdl-31543394

RESUMO

Giant cell arteritis (GCA) is a large-vessel vasculitis involving the aorta and its main branches, especially supra aortic branches. Although much progress has been made, the pathophysiology remains incompletely understood. An initial trigger, suspected of infectious origin, lead to the maturation and recruitment of dendritic cells (DC). The lack of migration of these DC allows the local recruitment of T-lymphocytes (LT). These LT- CD4+ polarize in Type 1 helper (Th1), Th17 but also Th9. A qualitative and quantitative deficit in regulatory T cells (Treg) is observed under the influence of IL-21 overproduction. In addition, an imbalance in the Th17/Treg balance is favored by IL-6. The secretion of IFN-γ, IL-17, IL-6, IL-33 is responsible for a sustained local inflammatory reaction that is organized around tertiary lymphoid follicles. Locally recruited macrophages secrete reactive forms of oxygen together with VEGF and PDGF. These growth factors, together with neurotrophins and endothelin contribute to increase the proliferation of vascular smooth muscle cells (VSMCs). The imbalance between matrix metalloproteases (MMP)-2, MMP-9 and MMP-14 and tissue inhibitors of metalloproteases (TIMP)-1 and TIMP-2 also contribute to the remodeling process occurring in the vessel wall. Finally, arterial neovascularization contribute to the perpetuation of lymphocyte recruitment. This persistent remodeling is sometimes complicated by ischemic events responsible for the initial severity of the disease.


Assuntos
Arterite de Células Gigantes/fisiopatologia , Remodelação Vascular/fisiologia , Animais , Linfócitos B/fisiologia , Linfócitos T CD4-Positivos/fisiologia , Movimento Celular , Proliferação de Células , Células Dendríticas/fisiologia , Modelos Animais de Doenças , Predisposição Genética para Doença , Arterite de Células Gigantes/tratamento farmacológico , Arterite de Células Gigantes/etiologia , Arterite de Células Gigantes/patologia , Humanos , Interferon gama/metabolismo , Interleucina-17/metabolismo , Interleucina-33/metabolismo , Interleucina-6/fisiologia , Interleucinas/biossíntese , Ativação Linfocitária/fisiologia , Macrófagos/metabolismo , Metaloproteinases da Matriz/metabolismo , Músculo Liso Vascular/patologia , Neovascularização Patológica/fisiopatologia , Linfócitos T Reguladores/fisiologia , Células Th17/fisiologia
3.
Life Sci ; 233: 116745, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31404524

RESUMO

Hypertension is one of the major risk factors for cardiovascular disease worldwide and is striking more young people, which is characterized by impaired vascular endothelial function. To find the functional lncRNAs associated with hypertension, high throughput lncRNA microarray were used to analyze expression profile of the lncRNAs in the aortic vascular endothelial cells (VECs) of spontaneously hypertensive rats (SHRs). The tail vein injection of siRNA was used to study the influence of lncRNA AK094457 inhibition on endothelial function in vivo. In vitro, endothelial function was studied in endothelial cells transfected with lncRNA AK094457-overexpressed vectors and siRNAs. pPPARγ and iNOS protein levels were detected with Western blot. Elisa assay was used to analyze the secretion of AngII, ET-1, ROS and LDH level. The nitrite/nitrate (NO2-/NO3-) concentration was measured using a colorimetric assay. LncRNA AK094457 was a most upregulated lncRNA in SHRs. It is showed that downregulation of AK094457 significantly reduced rat arterial pressure, increased activation of endothelial PPARγ, and suppressed serum contents of AngII and NO in vivo. Furthermore, results from gain-and-loss of function in primary aortic endothelial cells indicated that AK094457 negatively regulated activation of PPARγ and promoted AngII-mediated endothelial dysfunction, manifested by decreased capacities of cell proliferation and migration, and increased levels of ROS production and LDH release. In conclusion, lncRNA AK094457 is identified as a key regulator in blood pressure and endothelial function, which can increase AngII-induced hypertension and endothelial dysfunction via suppression of PPARγ.


Assuntos
Angiotensina II/toxicidade , Endotélio Vascular/patologia , Hipertensão/patologia , Músculo Liso Vascular/patologia , PPAR gama/antagonistas & inibidores , RNA Longo não Codificante/genética , Vasoconstritores/toxicidade , Animais , Proliferação de Células , Células Cultivadas , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Hipertensão/induzido quimicamente , Hipertensão/genética , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Ratos , Ratos Endogâmicos SHR , Transdução de Sinais , Remodelação Vascular
4.
Life Sci ; 237: 116769, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31422096

RESUMO

Hypoxic pulmonary hypertension (HPH) is a serious and potentially devastating disorder of the pulmonary circulation with complicated mechanisms. Long non-coding RNA (lncRNA) has been revealed to participate in HPH development. This study aimed to explore how lncRNA Tug1 affected the pulmonary vascular remodeling in HPH. A mouse model of HPH and a pulmonary artery smooth muscle cell (PASMC) model of HPH (HPH-PASMCs) were established, where the expression of lncRNA Tug1 was determined. Then, the interaction among lncRNA Tug1, miR-374c, and Foxc1 was assessed. Finally, in order to determine the effects of lncRNA Tug1 on PASMC activities and pulmonary vascular remodeling after HPH, the expression of lncRNA Tug1 was silenced in HPH-PASMCs and HPH mice, with the proliferation, apoptosis, and migration of PASMCs as well as blood pressure in mice measured, respectively. The obtained data revealed that lncRNA Tug1 was highly expressed in HPH mice and HPH-PASMCs. In addition, lncRNA Tug1 up-regulated the expression of Foxc1 by binding to miR-374c. Notably, silencing of lncRNA Tug1 inhibited the proliferation and migration, but promoted the apoptosis of PASMCs. Moreover, lncRNA Tug1 silencing was observed to attenuate the pulmonary vascular remodeling in HPH mice through the Foxc1-mediated NOTCH signaling pathway. Taken conjointly, silencing of lncRNA Tug1 down-regulated the Foxc1 expression by binding to miR-374c, thereby inhibiting the proliferation and migration, while promoting apoptosis of PASMCs to impede pulmonary vascular remodeling in HPH via the Notch signaling pathway. This study provided novel therapeutic insights for treating HPH.


Assuntos
Fatores de Transcrição Forkhead/metabolismo , Hipertensão Pulmonar/patologia , Hipóxia/fisiopatologia , MicroRNAs/genética , Músculo Liso Vascular/patologia , RNA Longo não Codificante/genética , Remodelação Vascular , Animais , Apoptose , Proliferação de Células , Células Cultivadas , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Artéria Pulmonar , Receptores Notch/genética , Receptores Notch/metabolismo , Transdução de Sinais
5.
Nat Commun ; 10(1): 2204, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101827

RESUMO

Pulmonary arterial hypertension (PAH) is a devastating disease with poor prognosis and limited therapeutic options. We screened for pathways that may be responsible for the abnormal phenotype of pulmonary arterial smooth muscle cells (PASMCs), a major contributor of PAH pathobiology, and identified cyclin-dependent kinases (CDKs) as overactivated kinases in specimens derived from patients with idiopathic PAH. This increased CDK activity is confirmed at the level of mRNA and protein expression in human and experimental PAH, respectively. Specific CDK inhibition by dinaciclib and palbociclib decreases PASMC proliferation via cell cycle arrest and interference with the downstream CDK-Rb (retinoblastoma protein)-E2F signaling pathway. In two experimental models of PAH (i.e., monocrotaline and Su5416/hypoxia treated rats) palbociclib reverses the elevated right ventricular systolic pressure, reduces right heart hypertrophy, restores the cardiac index, and reduces pulmonary vascular remodeling. These results demonstrate that inhibition of CDKs by palbociclib may be a therapeutic strategy in PAH.


Assuntos
Quinases Ciclina-Dependentes/antagonistas & inibidores , Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Animais , Linhagem Celular , Quinases Ciclina-Dependentes/metabolismo , Modelos Animais de Doenças , Hipertensão Pulmonar Primária Familiar/induzido quimicamente , Hipertensão Pulmonar Primária Familiar/patologia , Hipertensão Pulmonar Primária Familiar/cirurgia , Humanos , Indóis/toxicidade , Pulmão/irrigação sanguínea , Pulmão/patologia , Pulmão/cirurgia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monocrotalina/toxicidade , Músculo Liso Vascular/citologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Artéria Pulmonar/citologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Piridinas/uso terapêutico , Pirróis/toxicidade , Ratos , Ratos Endogâmicos WKY , Ratos Sprague-Dawley , Resultado do Tratamento
6.
Int J Mol Sci ; 20(9)2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31083380

RESUMO

Mitochondria-associated membranes (MAM) are a well-recognized contact link between the mitochondria and endoplasmic reticulum that affects mitochondrial biology and vascular smooth muscle cells (VSMCs) proliferation via the regulation of mitochondrial Ca2+(Ca2+m) influx. Nogo-B receptor (NgBR) plays a vital role in proliferation, epithelial-mesenchymal transition, and chemoresistance of some tumors. Recent studies have revealed that downregulation of NgBR, which stimulates the proliferation of VSMCs, but the underlying mechanism remains unclear. Here, we investigated the role of NgBR in MAM and VSMC proliferation. We analyzed the expression of NgBR in pulmonary arteries using a rat model of hypoxic pulmonary hypertension (HPH), in which rats were subjected to normoxic recovery after hypoxia. VSMCs exposed to hypoxia and renormoxia were used to assess the alterations in NgBR expression in vitro. The effect of NgBR downregulation and overexpression on VSMC proliferation was explored. The results revealed that NgBR expression was negatively related with VSMCs proliferation. Then, MAM formation and the phosphorylation of inositol 1,4,5-trisphosphate receptor type 3 (IP3R3) was detected. We found that knockdown of NgBR resulted in MAM disruption and augmented the phosphorylation of IP3R3 through pAkt, accompanied by mitochondrial dysfunction including decreased Ca2+m, respiration and mitochondrial superoxide, increased mitochondrial membrane potential and HIF-1α nuclear localization, which were determined by confocal microscopy and Seahorse XF-96 analyzer. By contrast, NgBR overexpression attenuated IP3R3 phosphorylation and HIF-1α nuclear localization under hypoxia. These results reveal that dysregulation of NgBR promotes VSMC proliferation via MAM disruption and increased IP3R3 phosphorylation, which contribute to the decrease of Ca2+m and mitochondrial impairment.


Assuntos
Membranas Mitocondriais/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Proteínas Nogo/metabolismo , Animais , Cálcio/metabolismo , Linhagem Celular , Proliferação de Células , Regulação para Baixo , Retículo Endoplasmático/metabolismo , Hipertensão Pulmonar , Hipóxia , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Masculino , Modelos Biológicos , Miócitos de Músculo Liso/ultraestrutura , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Artéria Pulmonar/metabolismo , Ratos , Transdução de Sinais
7.
EBioMedicine ; 43: 54-66, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31078518

RESUMO

BACKGROUND: Ascending aortic aneurysms constitute an important hazard for individuals with a bicuspid aortic valve (BAV). However, the processes that degrade the aortic wall in BAV disease remain poorly understood. METHODS: We undertook in situ analysis of ascending aortas from 68 patients, seeking potentially damaging cellular senescence cascades. Aortas were assessed for senescence-associated-ß-galactosidase activity, p16Ink4a and p21 expression, and double-strand DNA breaks. The senescence-associated secretory phenotype (SASP) of cultured-aged BAV aortic smooth muscle cells (SMCs) was evaluated by transcript profiling and consequences probed by combined immunofluorescence and circular polarization microscopy. The contribution of p38 MAPK signaling was assessed by immunostaining and blocking strategies. FINDINGS: We uncovered SMCs at varying depths of cellular senescence within BAV- and tricuspid aortic valve (TAV)-associated aortic aneurysms. Senescent SMCs were also abundant in non-aneurysmal BAV aortas but not in non-aneurysmal TAV aortas. Multivariable analysis revealed that BAV disease independently associated with SMC senescence. Furthermore, SMC senescence was heightened at the convexity of aortas associated with right-left coronary cusp fusion. Aged BAV SMCs had a pronounced collagenolytic SASP. Moreover, senescent SMCs in the aortic wall were enriched with surface-localized MMP1 and surrounded by weakly birefringent collagen fibrils. The senescent-collagenolytic SMC phenotype depended on p38 MAPK signaling, which was chronically activated in BAV aortas. INTERPRETATION: We have identified a cellular senescence-collagen destruction axis in at-risk ascending aortas. This novel "seno-destructive" SMC phenotype could open new opportunities for managing BAV aortopathy. FUND: Canadian Institutes of Health Research, Lawson Health Research Institute, Heart and Stroke Foundation of Ontario/Barnett-Ivey Chair.


Assuntos
Aorta/metabolismo , Aorta/patologia , Valva Aórtica/anormalidades , Doenças das Valvas Cardíacas/patologia , Miócitos de Músculo Liso/metabolismo , Idoso , Idoso de 80 Anos ou mais , Aneurisma Aórtico/etiologia , Aneurisma Aórtico/metabolismo , Aneurisma Aórtico/patologia , Valva Aórtica/patologia , Biomarcadores , Células Cultivadas , Senescência Celular , Colágeno/metabolismo , Quebras de DNA de Cadeia Dupla , Feminino , Doenças das Valvas Cardíacas/complicações , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Proteólise , Fatores de Risco
8.
Ren Fail ; 41(1): 220-228, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30973285

RESUMO

Vascular calcification (VC) is a pathological process characterized by abnormal deposition of calcium phosphate, hydroxyapatite and other mineral substances in the vascular wall. Hyperphosphorus is an important risk factor associated with VC in the general population and patients with chronic kidney disease (CKD). However, there is still a lack of early biomarkers for hyperphosphorus induced VC. We established a calcific rat aorta vascular smooth muscle cells (RASMCs) model by stimulating with ß-glycerophosphate. Then we performed label-free quantitative proteomics combined with liquid chromatograph-mass spectrometer/mass spectrometer (LC-2D-MS/MS)analysis and bioinformatics analysis to find the potential biomarkers for VC. In the current study, we identified 113 significantly proteins. Fifty six of these proteins were significantly up-regulated and the other 57 proteins were significantly decreased in calcific RASMCs, compared to that of normal control cells (fold-change (fc)>1.2, p < .05). Bioinformatics analysis indicated that these significant proteins mainly involved in the placenta blood vessel development and liver regeneration. Their molecule function was cell adhesion molecule binding. Among them, Smarca4 is significantly up-regulated in calcific RASMCs with fc = 2.72 and p = .01. In addition, we also established VC rat model. Real-time quantitative PCR analysis confirmed that the expression of Smarca4 was significantly increased in the aorta of calcified rat. Consistent with the up-regulation of Smarca4, the expression of VC associated microRNA such as miR-133b and miR-155 was also increased. Consequently, our study demonstrates that Smarca4 is involved in hyperphosphorus-induced VC. This finding may contribute to the early diagnosis and prevention of VC.


Assuntos
DNA Helicases/metabolismo , Hiperfosfatemia/metabolismo , Falência Renal Crônica/complicações , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Calcificação Vascular/metabolismo , Animais , Aorta/patologia , Biomarcadores/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Glicerofosfatos/toxicidade , Humanos , Falência Renal Crônica/induzido quimicamente , Falência Renal Crônica/metabolismo , Masculino , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Fosfatos/sangue , Fosfatos/metabolismo , Proteômica/instrumentação , Proteômica/métodos , Ratos , Ratos Wistar , Espectrometria de Massas em Tandem/instrumentação , Espectrometria de Massas em Tandem/métodos , Regulação para Cima , Calcificação Vascular/patologia
9.
Vasc Endovascular Surg ; 53(5): 379-386, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30982448

RESUMO

INTRODUCTION: Oral statins reduce intimal hyperplasia (IH) after arterial injury by only ∼25%. Alternative drug delivery systems have gained attention as carriers for hydrophobic drugs. We studied the effects of simvastatin (free vs hyaluronic acid-tagged polysialic acid-polycaprolactone micelles) on vascular smooth muscle cell (VSMC) migration, VSMC proliferation and intimal hyperplasia. We hypothesized both free and micelle containing simvastatin would inhibit VSMC chemotaxis and proliferation, and local statin treatment would be more effective than oral in reducing IH in rats following carotid balloon injury. METHODS: VSMCs pretreated with free simvastatin (20 minutes or 20 hours) or simvastatin-loaded micelles underwent chemotaxis and proliferation to platelet-derived growth factor. Next, rats that underwent balloon injury of the common carotid artery received statin therapy-intraluminal simvastatin-loaded micelles prior to injury, periadventitial pluronic gel following injury, or combinations of gel, micelle, and oral simvastatin. After 14 days, morphometric analysis determined the -intimal to medial ratio. Findings were compared to controls receiving oral simvastatin or no statin therapy. Statistical analysis was by analysis of variance for the in vitro experiments and a factorial general linear model for the in vivo experiments. RESULTS: The simvastatin-loaded micelles and free simvastatin inhibited VSMC chemotaxis (54%-60%). IH was induced in all injured vessels. Simvastatin in pluronic gel or micelles reduced IH compared to untreated controls (0.208 ± 0.04 or 0.160 ± 0.03 vs 0.350 ± 0.03, respectively); however, neither gel nor simvastatin-loaded micelles were superior to oral statins (0.261 ± 0.03). Addition of oral statins or combining both local therapies did not provide additional benefit. Micelles were the single greatest contributing factor in IH attenuation. CONCLUSIONS: Intraluminally or topically delivered statins reduced IH. The efficacy of single-dose, locally delivered statin alone may lead to novel treatments to prevent IH. The different routes of administration may allow for treatment during endovascular procedures, without the need for systemic therapy.


Assuntos
Lesões das Artérias Carótidas/tratamento farmacológico , Artéria Carótida Primitiva/efeitos dos fármacos , Portadores de Fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Neointima , Polímeros/química , Sinvastatina/administração & dosagem , Túnica Íntima/efeitos dos fármacos , Remodelação Vascular/efeitos dos fármacos , Administração Oral , Animais , Caproatos/química , Lesões das Artérias Carótidas/metabolismo , Lesões das Artérias Carótidas/patologia , Lesões das Artérias Carótidas/fisiopatologia , Artéria Carótida Primitiva/metabolismo , Artéria Carótida Primitiva/patologia , Artéria Carótida Primitiva/fisiopatologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Composição de Medicamentos , Humanos , Ácido Hialurônico/química , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Lactonas/química , Micelas , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Ratos Sprague-Dawley , Ácidos Siálicos/química , Sinvastatina/química , Túnica Íntima/metabolismo , Túnica Íntima/patologia , Túnica Íntima/fisiopatologia
10.
Pharmazie ; 74(3): 168-174, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30961684

RESUMO

Inflammation and vascular smooth muscle cells (VSMCs) play key roles in the development of many cardiovascular diseases (CVDs). Although vitamin D decreases the risks of inflammation related diseases including CVDs, the links between vitamin D, VSMCs and vascular inflammation remained unclear. In this study, we investigated the anti-inflammatory effect and signaling pathways of vitamin D in lipopolysaccharide (LPS)-induced VSMCs. 1,25(OH)2D3 treatment inhibited the significant upregulation of COX-2, PGE2, TNF-α and IL-6 and p38 phosphorylation induced by LPS in A10 cells. Blocking p38 signaling attenuated the inhibitory effect of 1,25(OH)2D3 on the upregulation of COX-2 and phosphorylation of p38. These results indicate 1,25(OH)2D3 suppresses inflammatory response in LPS-induced VSMCs through p38 MAPK signaling pathway.


Assuntos
Calcitriol/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Células Cultivadas , Ciclo-Oxigenase 2/biossíntese , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dinoprostona/antagonistas & inibidores , Dinoprostona/biossíntese , Dinoprostona/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/enzimologia , Inflamação/patologia , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/patologia , NF-kappa B/metabolismo , Fosforilação , Ratos , Fator de Necrose Tumoral alfa/metabolismo
11.
Eur J Pharmacol ; 854: 213-223, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-30940448

RESUMO

Vascular smooth muscle cell (VSMC) proliferation and migration are crucial events in the pathological course of atherosclerosis and restenosis after percutaneous coronary intervention (PCI). Dioscin has been shown to exhibit powerful cardiovascular protective effects and potent therapeutic potential in cancer owing to the inhibition of cell proliferation and migration. However, its effects on arterial wall hypertrophy-related diseases caused by VSMC proliferation and migration remain unclear. In this study, we investigated the effects of dioscin on intimal hyperplasia after balloon injury in vivo, its effects on VSMC proliferation and migration in vitro, and the mechanisms underlying these effects. Results showed that dioscin treatment significantly inhibited VSMC proliferation and intimal thickening after balloon injury. In cultured VSMCs, treatment with dioscin significantly decreased fetal bovine serum or platelet-derived growth factor-induced cell proliferation and migration. Moreover, dioscin inhibited the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and expression of Forkhead box M1 (FoxM1) and its downstream target genes. FoxM1 knockdown with shRNA partially counteracted the inhibitory effects of dioscin on cell proliferation and migration. In conclusion, we demonstrated that dioscin attenuated neointima formation in response to balloon injury by suppressing VSMC proliferation and migration through MAPK-FoxM1 pathway. Our data suggested that dioscin might be a potential therapeutic agent for atherosclerosis and restenosis after PCI.


Assuntos
Lesões das Artérias Carótidas/patologia , Diosgenina/análogos & derivados , Proteína Forkhead Box M1/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Túnica Íntima/efeitos dos fármacos , Túnica Íntima/patologia , Animais , Lesões das Artérias Carótidas/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diosgenina/farmacologia , Diosgenina/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Hiperplasia/tratamento farmacológico , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Músculo Liso Vascular/patologia , Fenótipo , Ratos , Ratos Sprague-Dawley
12.
Oxid Med Cell Longev ; 2019: 3415682, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31007833

RESUMO

Aims: Vascular calcification (VC) is a primary risk factor for cardiovascular mortality in chronic renal failure (CRF) patients; thus, effective therapeutic targets are urgently needed to be explored. Here, we identified the role of intestinal bacterial translocation in CRF-related VC. Methods and Results: Antibiotic supplementation by oral gavage significantly suppressed intestinal bacterial translocation, CRF-related VC, and aortic osteogenic gene and Toll-like receptor (TLR) gene expression in CRF rats. Furthermore, TLR4 and TLR9 activation in vascular smooth muscle cells (VSMCs) aggravated inorganic phosphate- (Pi-) induced calcification. TLR9 inhibition, but not TLR4 inhibition, by both a pharmacological inhibitor and genetic methods could significantly reduce CRF rats' serum or CRF-induced VC. Interestingly, bone morphogenic protein-2 (BMP-2) levels were increased in the aorta and sera from CRF rats. Increased BMP-2 levels were also observed in VSMCs treated with TLR9 agonist, which was blocked by NF-κB inhibition. Both siRNA knockdown of BMP-2 and NF-κB inhibitor significantly blocked TLR9 agonist-induced VSMC calcification. Conclusions: Gut bacterial translocation inhibited by oral antibiotic significantly reduces CRF-related VC through inhibition of TLR9/NF-κB/BMP-2 signaling.


Assuntos
Translocação Bacteriana , Proteína Morfogenética Óssea 2/metabolismo , Microbioma Gastrointestinal , Receptor Toll-Like 9/metabolismo , Calcificação Vascular/metabolismo , Calcificação Vascular/microbiologia , Animais , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Translocação Bacteriana/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , DNA Bacteriano/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Inflamação/patologia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , NF-kappa B/metabolismo , Osteoblastos/citologia , Ratos Wistar , Insuficiência Renal Crônica/microbiologia , Insuficiência Renal Crônica/patologia , Transdução de Sinais
13.
J Vasc Surg ; 69(5): 1581-1589.e1, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31010523

RESUMO

OBJECTIVE: Current drug-eluting stent (DES) treatment is promising, but it still has the drawback of in-stent restenosis, which remains a clinically relevant problem. Efforts should be made to discover new signaling molecules and novel potential targets for the prevention of arterial restenosis. In this study, we fabricated a novel DES targeting the RhoA pathway and further examined this promising strategy in vitro and in a rabbit carotid model. METHODS: Active RhoA expression is correlated with the synthetic smooth muscle phenotype, and the RhoA inhibitor rhosin suppresses this phenotypic modulation at both transcriptional and translational levels. We further demonstrated that the RhoA inhibitor rhosin might act through the YAP pathway in smooth muscle cell phenotype modulation by a gain-of-function assay. Moreover, we fabricated a RhoA inhibitor-eluting stent and tested it in a rabbit carotid model. RESULTS: Compared with a bare-metal stent, the RhoA inhibitor-eluting stent significantly attenuated neointimal formation at 6 months. However, overexpression of YAP by lentivirus blocked the antirestenosis effect of the RhoA inhibitor-eluting stent and repressed smooth muscle-specific genes. CONCLUSIONS: RhoA inhibitor-eluting stents attenuate neointimal formation through inhibition of the YAP signaling pathway. This novel DES may represent a potential strategy for the treatment of in-stent restenosis.


Assuntos
Angioplastia com Balão/instrumentação , Proliferação de Células/efeitos dos fármacos , Stents Farmacológicos , Inibidores Enzimáticos/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Compostos Orgânicos/farmacologia , Proteínas Proto-Oncogênicas c-yes/metabolismo , Proteínas rho de Ligação ao GTP/antagonistas & inibidores , Angioplastia com Balão/efeitos adversos , Animais , Apoptose/efeitos dos fármacos , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/enzimologia , Artérias Carótidas/patologia , Células Cultivadas , Constrição Patológica , Masculino , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/patologia , Neointima , Proteínas Proto-Oncogênicas c-yes/genética , Coelhos , Ratos , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Proteínas rho de Ligação ao GTP/metabolismo
14.
Life Sci ; 224: 51-57, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30905780

RESUMO

The pathogenesis of abdominal aortic aneurysm remains unclear. The aim of the present study was to establish whether isoleucyl-tRNA synthetase (Iars) regulates the differentiation and apoptosis of vascular smooth muscle cells (VSMCs) during the development of abdominal aortic aneurysm (AAA). In addition, the contribution of various signaling pathways towards this process was ascertained. The study demonstrated that the expression of Iars, p-p38, osteopontin (OPN) and Bcl-2-associated X protein (Bax) clearly increased, while levels of p-PI3K and smooth muscle 22 alpha (SM22α) decreased significantly in AAA tissues. Inhibition of Iars significantly reduced the incidence of angiotensin II (AngII)-induced AAA in mice, coincident with decreased activity of the p38 MAPK pathway and increased PI3K pathway activity. AngII-induced phenotypic switching and apoptosis of VSMCs decreased following the inhibition of Iars in vitro. Upregulation of the IARS gene induced phenotypic switching and apoptosis in VSMCs in addition to increased p38 MAPK pathway activation and reduced PI3K pathway activation. Following pretreatment with an activator of the PI3K pathway, expression of Iars and the phenotypic markers of VSMCs were not affected, while apoptosis of VSMCs decreased. Similarly, inhibition of the p38 MAPK pathway in VSMCs did not affect the expression of Iars or the degree of cell apoptosis, but reduced phenotypic switching was observed. Conclusively, upregulation of Iars regulates the phenotypic switching and apoptosis of VSMCs. Targeting Iars may be a promising strategy to prevent abdominal aortic aneurysm.


Assuntos
Aneurisma da Aorta Abdominal/patologia , Apoptose , Regulação da Expressão Gênica , Isoleucina-tRNA Ligase/metabolismo , Músculo Liso Vascular/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Aneurisma da Aorta Abdominal/metabolismo , Proliferação de Células , Células Cultivadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Transdução de Sinais
15.
Microvasc Res ; 124: 43-50, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30853343

RESUMO

Pulmonary arterial hypertension (PAH) is a devastating and fatal vascular disease for which currently there is no satisfying therapy available. Excessive cell proliferation of pulmonary arterial smooth muscle cells (PASMCs) contributes significantly to PAH pathogenesis. In this study, we found that miR-205-5p was lowly expressed in hypoxia-induced PAH mouse model and hypoxia-treated PASMCs. Restoration of miR-205-5p suppressed PASMCs proliferation. In contrast, molecule interacting with CasL 2 (MICAL2) was highly expressed in hypoxia-induced PAH mouse model and hypoxia-treated PASMCs. Overexpression of MICAL2 promoted cell proliferation. Furthermore, miR-205-5p inhibited MICAL2 expression levels by targeting the MICAL2 3' untranslated region. In addition, MICAL2 activated ERK1/2 signaling in PASMCs and ERK1/2 inhibitor blocked MICAL2-mediated-promotion effect on PASMCs proliferation. These results demonstrated that miR-205-5p suppressed PASMCs proliferation by targeting MICAL2, which activated ERK1/2 signaling. Therefore, miR-205-5p/MICAL2/Erk1/2 may serve as an ideal therapeutic target to PAH treatment.


Assuntos
Proliferação de Células , Proteínas do Citoesqueleto/metabolismo , Hipertensão Pulmonar/enzimologia , MicroRNAs/metabolismo , Proteínas dos Microfilamentos/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Oxirredutases/metabolismo , Animais , Células Cultivadas , Proteínas do Citoesqueleto/genética , Modelos Animais de Doenças , Humanos , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/patologia , Hipóxia/complicações , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Proteínas dos Microfilamentos/genética , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Oxirredutases/genética , Artéria Pulmonar/enzimologia , Artéria Pulmonar/patologia , Transdução de Sinais , Remodelação Vascular
16.
Cell Mol Life Sci ; 76(11): 2077-2091, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30887097

RESUMO

Medial vascular calcification has emerged as a putative key factor contributing to the excessive cardiovascular mortality of patients with chronic kidney disease (CKD). Hyperphosphatemia is considered a decisive determinant of vascular calcification in CKD. A critical role in initiation and progression of vascular calcification during elevated phosphate conditions is attributed to vascular smooth muscle cells (VSMCs), which are able to change their phenotype into osteo-/chondroblasts-like cells. These transdifferentiated VSMCs actively promote calcification in the medial layer of the arteries by producing a local pro-calcifying environment as well as nidus sites for precipitation of calcium and phosphate and growth of calcium phosphate crystals. Elevated extracellular phosphate induces osteo-/chondrogenic transdifferentiation of VSMCs through complex intracellular signaling pathways, which are still incompletely understood. The present review addresses critical intracellular pathways controlling osteo-/chondrogenic transdifferentiation of VSMCs and, thus, vascular calcification during hyperphosphatemia. Elucidating these pathways holds a significant promise to open novel therapeutic opportunities counteracting the progression of vascular calcification in CKD.


Assuntos
Hiperfosfatemia/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Insuficiência Renal Crônica/metabolismo , Transdução de Sinais , Calcificação Vascular/metabolismo , Animais , Fosfatos de Cálcio/química , Fosfatos de Cálcio/metabolismo , Transdiferenciação Celular , Condrócitos/metabolismo , Condrócitos/patologia , Regulação da Expressão Gênica , Humanos , Hiperfosfatemia/complicações , Hiperfosfatemia/genética , Hiperfosfatemia/patologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , NF-kappa B/genética , NF-kappa B/metabolismo , Osteoblastos/metabolismo , Osteoblastos/patologia , Ligante RANK/genética , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/genética , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Calcificação Vascular/complicações , Calcificação Vascular/genética , Calcificação Vascular/patologia
17.
Respir Res ; 20(1): 42, 2019 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-30813929

RESUMO

BACKGROUND: Obesity is associated with cardiovascular complications, including pulmonary hypertension (PH). Reports suggest that peroxisome proliferator-activated receptor-γ (PPARγ) has direct action in preventing vascular remodelling in PH. Here we dissected the specific role of high-fat-diet (HFD)-induced obesity and vascular smooth muscle cell (VSMC)-PPARγ for remodelling of small pulmonary arteries. METHODS: Wild-type (WT) and VSMC-specific PPARγ-knockout (SmPparγ-/-) mice were fed a low-fat-diet (LFD, 10% kcal from fat) or HFD (60% kcal from fat) for 24 weeks. Mice were metabolically phenotyped (e.g. weight development, insulin/glucose tolerance) at the beginning, and after 12 and 24 weeks, respectively. At 24 weeks additionally pulmonary pressure, heart structure, pulmonary vascular muscularization together with gene and protein expression in heart and lung tissues were determined. RESULTS: HFD increased right ventricular systolic pressure (RVSP) to a similar extent in WT and SmPparγ-/- mice. HFD decreased glucose tolerance and insulin sensitivity in both WT and SmPparγ-/- mice. Importantly, the increase in RVSP correlated with the degree of insulin resistance. However, VSMC-PPARγ deficiency increased pulmonary vascular muscularization independently of the diet-induced rise in RVSP. This increase was associated with elevated expression of early growth response protein 1 in heart and osteopontin in lung tissue. CONCLUSIONS: Here we demonstrate a correlation of insulin resistance and pulmonary pressure. Further, deficiency of PPARγ in VSMCs diet-independently leads to increased pulmonary vascular muscularization.


Assuntos
Hipertensão Pulmonar/metabolismo , Músculo Liso Vascular/metabolismo , Obesidade/metabolismo , PPAR gama/deficiência , Artéria Pulmonar/metabolismo , Remodelação Vascular/fisiologia , Animais , Células Cultivadas , Dieta Hiperlipídica/efeitos adversos , Hipertensão Pulmonar/patologia , Resistência à Insulina/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/patologia , Obesidade/patologia , Artéria Pulmonar/patologia , Distribuição Aleatória
18.
Respir Res ; 20(1): 53, 2019 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-30857524

RESUMO

BACKGROUND: In this study, we aimed to investigate whether and how lncRNA CASC2 was involved in hypoxia-induced pulmonary hypertension (PH)-related vascular remodeling. METHODS: The expression of lncRNAs or mRNAs was detected by qRT-PCR, and western blot analysis or immunochemistry was employed for detecting the protein expression. Cell number assay and EdU (5-ethynyl-2'-deoxyuridine) staining were performed to assess cell proliferation. Besides, flow cytometry and wound healing assay were employed for assessments of cell apoptosis and cell migration, respectively. Rat model of hypoxic PH was established and the hemodynamic measurements were performed. Hematoxylin and eosin (HE) and Masson's trichrome staining were carried out for pulmonary artery morphometric analysis. RESULTS: The expression of lncRNA CASC2 was decreased in hypoxia-induced rat pulmonary arterial tissues and pulmonary artery smooth muscle cells (PASMCs). Up-regulation of lncRNA CASC2 inhibited cell proliferation, migration yet enhanced apoptosis in vitro and in vivo in hypoxia-induced PH. Western blot analysis and immunochemistry showed that up-regulation of lncRNA CASC2 greatly decreased the expression of phenotype switch-related marker α-SMA in hypoxia-induced PH. Furthermore, it was indicated by the pulmonary artery morphometric analysis that lncRNA CASC2 suppressed vascular remodeling of hypoxia-induced rat pulmonary arterial tissues. CONCLUSION: LncRNA CASC2 inhibited cell proliferation, migration and phenotypic switch of PASMCs to inhibit the vascular remodeling in hypoxia-induced PH.


Assuntos
Proliferação de Células/fisiologia , Hipertensão Pulmonar/metabolismo , Hipóxia/metabolismo , Músculo Liso Vascular/metabolismo , RNA Longo não Codificante/biossíntese , Proteínas Supressoras de Tumor/biossíntese , Animais , Células Cultivadas , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/patologia , Hipóxia/complicações , Hipóxia/patologia , Masculino , Músculo Liso Vascular/patologia , Fenótipo , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Ratos , Ratos Wistar
19.
Vascul Pharmacol ; 114: 13-22, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30910127

RESUMO

The advent of deep sequencing technologies recently unraveled the complexity of the human genome: Although almost entirely transcribed, only a very minor part of our genome actually accounts for protein coding exons and most is considered non-coding. Among the non-coding transcripts, long non-coding RNAs (lncRNAs) constitute a rather heterogeneous group of linear as well as circular RNAs (circRNAs). LncRNAs act via multiple mechanisms and several lncRNAs were shown to be involved in vascular development, growth and remodeling. For example, the lncRNAs PUNISHER, MALAT1, MEG3, and GATA6-AS regulate vessel formation in vivo, whereas lincRNA-p21 controls smooth muscle cell function and neointima formation. For several other lncRNAs (e.g. SENCR, SMILR, and HypERlnc) functional roles in smooth muscle cells/pericytes have been described in vitro. Less information is available with respect to the function of circRNAs. Here most studies report on expression profiles but some circRNAs (e.g. cANRIL or cZNF292) may also play critical roles in smooth muscle or endothelial cells in vitro. This review summarizes the current knowledge of lncRNA and circRNA functions in vascular biology and disease and discusses their potential use as biomarkers.


Assuntos
Aterosclerose/metabolismo , Vasos Sanguíneos/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Aterosclerose/genética , Aterosclerose/patologia , Vasos Sanguíneos/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Regulação da Expressão Gênica , Marcadores Genéticos , Humanos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , RNA Longo não Codificante/genética , Transdução de Sinais
20.
Vascul Pharmacol ; 114: 23-30, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30910128

RESUMO

In recent years, it has been revealed that majority of the genome is transcribed in a cell- and context-specific manner into a vast array of RNA transcripts that do not encode proteins. Increasing evidence suggests that non-coding RNAs, especially long non-coding RNAs (lncRNAs) are essential regulators of gene expression and other cellular processes, including in the cardiovascular context. In this review, we discuss lncRNAs and their function during endothelial and vascular smooth cell differentiation, function and homeostasis as well as their role in vessel wall injury response and vascular disease pathophysiology. Although our understanding of lncRNAs is still emerging, these examples reveal important insights on how lncRNAs may ultimately be used in clinic as therapeutic targets for cardiovascular disease.


Assuntos
Vasos Sanguíneos/metabolismo , Doenças Cardiovasculares/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Vasos Sanguíneos/patologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Diferenciação Celular , Células Endoteliais/metabolismo , Regulação da Expressão Gênica , Humanos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Neovascularização Fisiológica , RNA Longo não Codificante/genética , Transdução de Sinais , Remodelação Vascular
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA