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1.
Int J Mol Sci ; 22(2)2021 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-33467058

RESUMO

Vascular dysfunction in cardiovascular diseases includes vasomotor response impairments, endothelial cells (ECs) activation, and smooth muscle cells (SMCs) proliferation and migration to the intima. This results in intimal hyperplasia and vessel failure. We previously reported that activation of the P2Y11 receptor (P2Y11R) in human dendritic cells, cardiofibroblasts and cardiomyocytes was protective against hypoxia/reoxygenation (HR) lesions. In this study, we investigated the role of P2Y11R signaling in vascular dysfunction. P2Y11R activity was modulated using its pharmacological agonist NF546 and antagonist NF340. Rat aortic rings were exposed to angiotensin II (AngII) and evaluated for their vasomotor response. The P2Y11R agonist NF546 reduced AngII-induced vascular dysfunction by promoting EC-dependent vasorelaxation, through an increased nitric oxide (NO) bioavailability and reduced AngII-induced H2O2 release; these effects were prevented by the use of the P2Y11R antagonist NF340. Human vascular SMCs and ECs were subjected to AngII or H/R simulation in vitro. P2Y11R agonist modulated vasoactive factors in human ECs, that is, endothelial nitric oxide synthase (eNOS) and endothelin-1, reduced SMC proliferation and prevented the switch towards a synthetic phenotype. H/R and AngII increased ECs secretome-induced SMC proliferation, an effect prevented by P2Y11R activation. Thus, our data suggest that P2Y11R activation may protect blood vessels from HR-/AngII-induced injury and reduce vascular dysfunctions. These results open the way for new vasculoprotective interventions.


Assuntos
Difosfonatos/farmacologia , Naftalenossulfonatos/farmacologia , Agonistas do Receptor Purinérgico P2/farmacologia , Receptores Purinérgicos P2/metabolismo , Traumatismo por Reperfusão/metabolismo , Túnica Íntima/patologia , Angiotensina II/toxicidade , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Aorta/fisiopatologia , Difosfonatos/uso terapêutico , Endotelina-1/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Hiperplasia/prevenção & controle , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Naftalenossulfonatos/uso terapêutico , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Agonistas do Receptor Purinérgico P2/uso terapêutico , Ratos , Ratos Wistar , Traumatismo por Reperfusão/tratamento farmacológico , Túnica Íntima/efeitos dos fármacos , Túnica Íntima/metabolismo , Vasodilatação , Água/metabolismo
2.
Arq. bras. cardiol ; 115(4): 630-636, out. 2020. graf
Artigo em Português | LILACS, Sec. Est. Saúde SP | ID: biblio-1131353

RESUMO

Resumo Fundamento: A taxa de falha de enxerto de veia safena um ano após a cirurgia de revascularização do miocárdio varia de 10% a 25%. O objetivo deste estudo foi de investigar se a atorvastatina pode reduzir o acúmulo de células musculares lisas vasculares para inibir a hiperplasia intimal por meio da inibição da via p38 MAPK. Métodos: Quarenta e cinco ratos Sprague-Dawley foram randomizados em três grupos. Trinta ratos foram submetidos à cirurgia de enxerto de veia e randomizados para tratamento com veículo ou atorvastatina; quinze ratos foram submetidos à cirurgia sham. Detectamos a hiperplasia intimal por meio de coloração com hematoxilina-eosina e a expressão de proteínas relacionadas por meio de análise imuno-histoquímica e Western blot. Foram realizadas as comparações por análise de variância de fator único e pelo teste da diferença mínima significativa de Fisher, com p < 0,05 considerado significativo. Resultados: A íntima analisada pela coloração com hematoxilina-eosina era dramaticamente mais espessa no grupo controle que no grupo atorvastatina e no grupo sham (p < 0,01). Os resultados da coloração imuno-histoquímica de α-SMA demonstraram que a porcentagem de células positivas para α-SMA no grupo controle era mais alta que no grupo atorvastatina (p < 0,01). Nós também avaliamos α-SMA, PCNA, p38 MAPK e fosforilação de p38 MAPK após o tratamento com estatina por meio de análise de Western blot e os resultados indicaram que a atorvastatina não levou à redução de p38 MAPK (p < 0,05); no entanto, resultou na inibição da fosforilação de p38 MAPK (p < 0,01) e reduziu significativamente os níveis de α-SMA e PCNA, em comparação com o grupo controle (p < 0,01). Conclusão: Nós demonstramos que a atorvastatina pode inibir o acúmulo de células musculares lisas vasculares por meio da inibição da via p38 MAPK e é capaz de inibir a hiperplasia intimal em modelos de enxerto de veia em ratos.


Abstract Background: The rate of saphenous vein graft failure one year after coronary artery bypass grafting ranges from 10% to 25%. The aim of this study was to explore whether atorvastatin can reduce accumulation of vascular smooth muscle cells to inhibit intimal hyperplasia via p38 MAPK pathway inhibition. Methods: Forty-five Sprague-Dawley rats were randomized to three groups. Thirty rats received a vein graft operation, and they were randomized to be treated with vehicle or atorvastatin; fifteen rats received a sham operation. We detected intimal hyperplasia by hematoxylin-eosin staining and related protein expression by immunohistochemical and Western blot analysis. Comparisons were analyzed by single-factor analysis of variance and Fisher's least significant difference test, with p < 0.05 considered significant. Results: The intima analyzed by hematoxylin-eosin staining was dramatically thicker in the control group than in the atorvastatin group and sham group (p < 0.01). The outcomes of immunohistochemical staining of α-SMA demonstrated that the percentage of α-SMA-positive cells in the control group was higher than in the atorvastatin group (p < 0.01). We also evaluated α-SMA, PCNA, p38 MAPK, and phosphorylation of p38 MAPK after statin treatment by Western blot analysis, and the results indicated that atorvastatin did not lead to p38 MAPK reduction (p < 0.05); it did, however, result in inhibition of p38 MAPK phosphorylation (p < 0.01), and it significantly reduced α-SMA and PCNA levels, in comparison with the control group (p < 0.01). Conclusion: We have demonstrated that atorvastatin can inhibit accumulation of vascular smooth muscle cells by inhibiting the p38 MAPK pathway, and it is capable of inhibiting intimal hyperplasia in a rat vein graft model.


Assuntos
Animais , Ratos , Transplantes , Proteínas Quinases p38 Ativadas por Mitógeno , Veias , Ratos Sprague-Dawley , Atorvastatina/uso terapêutico , Atorvastatina/farmacologia , Hiperplasia/prevenção & controle , Hiperplasia/tratamento farmacológico , Músculo Liso Vascular
3.
PLoS One ; 15(4): e0232428, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32343734

RESUMO

BACKGROUND: Elevated parathyroid hormone (PTH) levels in secondary hyperparathyroidism (SHPT) lead to vascular calcification, which is associated with cardiovascular events and mortality. Increased PTH production is caused by the excessive proliferation of parathyroid gland cells, which is accelerated by abnormal mineral homeostasis. Evocalcet, an oral calcimimetic agent, inhibits the secretion of PTH from parathyroid gland cells and has been used for the management of SHPT in dialysis patients. We observed the effects of evocalcet on ectopic calcification and parathyroid hyperplasia using chronic kidney disease (CKD) rats with SHPT. METHODS: CKD rats with SHPT induced by adenine received evocalcet orally for 5 weeks. The calcium and inorganic phosphorus content in the aorta, heart and kidney was measured. Ectopic calcified tissues were also assessed histologically. To observe the effects on the proliferation of parathyroid gland cells, parathyroid glands were histologically assessed in CKD rats with SHPT induced by 5/6 nephrectomy (Nx) after receiving evocalcet orally for 4 weeks. RESULTS: Evocalcet prevented the increase in calcium and inorganic phosphorus content in the ectopic tissues and suppressed calcification of the aorta, heart and kidney in CKD rats with SHPT by reducing the serum PTH and calcium levels. Evocalcet suppressed the parathyroid gland cell proliferation and reduced the sizes of parathyroid cells in CKD rats with SHPT. CONCLUSIONS: These findings suggest that evocalcet would prevent ectopic calcification and suppress parathyroid hyperplasia in patients with SHPT.


Assuntos
Hiperparatireoidismo Secundário/complicações , Naftalenos/uso terapêutico , Glândulas Paratireoides/patologia , Pirrolidinas/uso terapêutico , Calcificação Vascular/prevenção & controle , Animais , Calcimiméticos/uso terapêutico , Hiperplasia/etiologia , Hiperplasia/prevenção & controle , Masculino , Ratos , Ratos Sprague-Dawley , Calcificação Vascular/etiologia
4.
PLoS Biol ; 18(2): e3000603, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32092075

RESUMO

Type 2 diabetes (T2D) is characterized by insulin resistance along with pancreatic ß cell failure. ß cell factors are traditionally thought to control glucose homeostasis by modulating insulin levels, not insulin sensitivity. Exosomes are emerging as new regulators of intercellular communication. However, the role of ß-cell-derived exosomes in metabolic homeostasis is poorly understood. Here, we report that microRNA-26a (miR-26a) in ß cells not only modulates insulin secretion and ß cell replication in an autocrine manner but also regulates peripheral insulin sensitivity in a paracrine manner through circulating exosomes. MiR-26a is reduced in serum exosomes of overweight humans and is inversely correlated with clinical features of T2D. Moreover, miR-26a is down-regulated in serum exosomes and islets of obese mice. Using miR-26a knockin and knockout mouse models, we showed that miR-26a in ß cells alleviates obesity-induced insulin resistance and hyperinsulinemia. Mechanistically, miR-26a in ß cells enhances peripheral insulin sensitivity via exosomes. Meanwhile, miR-26a prevents hyperinsulinemia through targeting several critical regulators of insulin secretion and ß cell proliferation. These findings provide a new paradigm for the far-reaching systemic functions of ß cells and offer opportunities for the treatment of T2D.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , MicroRNAs/metabolismo , Animais , Proliferação de Células , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Exossomos/metabolismo , Expressão Gênica , Regulação da Expressão Gênica , Glucose/metabolismo , Humanos , Hiperinsulinismo/prevenção & controle , Hiperplasia/prevenção & controle , Insulina/metabolismo , Células Secretoras de Insulina/patologia , Masculino , Camundongos , Camundongos Obesos , Camundongos Transgênicos , MicroRNAs/sangue , MicroRNAs/genética , Comunicação Parácrina , Transdução de Sinais
5.
Int J Mol Sci ; 21(3)2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32023822

RESUMO

Proton pump inhibitor use is associated with an increased risk of gastric cancer, which may be mediated by hypergastrinemia. Spasmolytic polypeptide-expression metaplasia (SPEM) has been proposed as a precursor of gastric cancer. We have examined the effects of the gastrin receptor antagonist netazepide (NTZ) or vehicle on the gastric corpus mucosa of H+/K+ATPase beta subunit knockout (KO) and wild-type (WT) mice. The gastric corpus was evaluated by histopathology, immunohistochemistry (IHC), in situ hybridization (ISH) and whole-genome gene expression analysis, focusing on markers of SPEM and neuroendocrine (NE) cells. KO mice had pronounced hypertrophy, intra- and submucosal cysts and extensive expression of SPEM and NE cell markers in the gastric corpus, but not in the antrum. Numerous SPEM-related genes were upregulated in KO mice compared to WT mice. NTZ reduced hypertrophia, cysts, inflammation and NE hyperplasia. However, NTZ neither affected expression of SPEM markers nor of SPEM-related genes. In conclusion, NTZ prevented mucosal hypertrophy, cyst formation and NE cell hyperplasia but did not affect SPEM. The presence of SPEM seems unrelated to the changes caused by hypergastrinemia in this animal model.


Assuntos
Benzodiazepinonas/administração & dosagem , Mucosa Gástrica/patologia , ATPase Trocadora de Hidrogênio-Potássio/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Células Neuroendócrinas/patologia , Compostos de Fenilureia/administração & dosagem , Animais , Benzodiazepinonas/farmacologia , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , ATPase Trocadora de Hidrogênio-Potássio/metabolismo , Humanos , Hiperplasia/prevenção & controle , Hibridização In Situ , Injeções Subcutâneas , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Metaplasia , Camundongos , Camundongos Knockout , Compostos de Fenilureia/farmacologia , Sequenciamento Completo do Exoma
6.
J Surg Res ; 246: 550-559, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31668608

RESUMO

BACKGROUND: Intimal hyperplasia (IH) is the initial lesion of vein graft failure after coronary artery bypass grafting. The weak venous wall is likely one of the primary reasons for IH after exposure to the arterial environment. We investigate whether adventitial collagen cross-link by glutaraldehyde (GA) reinforces the venous wall and then reduces IH. MATERIALS AND METHODS: Adventitial collagen cross-link by 0.3% GA was performed on the rabbit jugular veins. The degree of cross-link was accessed by tensile test. The jugular vein with or without cross-link was implanted into the carotid artery of rabbit. Vein dilatation at the immediate anastomosis and pathological remodeling of vein graft after 4 wk was assessed. RESULTS: Tensile test indicated that the mechanical property of 3-min cross-linked veins more closely resembled that of the carotid artery. In rabbit arteriovenous graft models, 3-min adventitial collagen cross-link limited overdistension (diameter: 3.24 mm versus 4.65 mm, P < 0.01) at the immediate anastomosis and reduced IH (intima thickness: 78.83 µm versus 140.19 µm, P < 0.01) of vein grafts 4 wk after implantation in the cross-link group as compared with the graft group (without cross-link). Compared with the cross-link group, the expression of proliferating cell nuclear antigen and vascular cell adhesion molecule-1 increased significantly at both the mRNA and protein levels within the graft group (P < 0.01), but the expression of smooth muscle-22α decreased significantly (P < 0.01). CONCLUSIONS: Adventitial collagen cross-link by GA increased the vessel stiffness and remarkably reduced IH in a rabbit arteriovenous graft model.


Assuntos
Túnica Adventícia/efeitos dos fármacos , Colágeno/metabolismo , Reagentes para Ligações Cruzadas/administração & dosagem , Glutaral/administração & dosagem , Túnica Íntima/patologia , Túnica Adventícia/metabolismo , Animais , Artérias Carótidas/transplante , Ponte de Artéria Coronária/efeitos adversos , Modelos Animais de Doenças , Humanos , Hiperplasia/etiologia , Hiperplasia/prevenção & controle , Veias Jugulares/efeitos dos fármacos , Veias Jugulares/transplante , Masculino , Coelhos , Túnica Íntima/efeitos dos fármacos , Túnica Íntima/metabolismo , Rigidez Vascular/efeitos dos fármacos
7.
Urolithiasis ; 48(1): 47-56, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30259058

RESUMO

Ureteric stents have become an indispensable tool in the armamentarium of every urologist. However, they carry their own morbidity resulting mostly from infectious or abacterial fouling and biofilm formation, and/or urothelial hyperplastic reaction. All of these may interact and lead to clinical complications. Many different stent designs and coatings have been proposed. In this study, we focused on the effect of paclitaxel-coated stents on hyperplastic proliferation of ureteral tissue, using as example anastomotic strictures after ureteroureterostomy in a rat model. Human urothelial cells (SV-HUC-1) were used to determine paclitaxel dosages in vitro. Polyurethane stents were coated with a paclitaxel containing biodegradable polymer and studied in a ureteroureterostomy rat model. 48 male 9-week-old Sprague-Dawley rats underwent either sham surgery (n = 16) or ureteroureterostomy with sutured anastomosis, and consecutive stenting with either a paclitaxel-coated or an uncoated stent (16 per group), respectively. The animals received daily intraperitoneal injections of 5-bromo-2-deoxyuridine (20 mg/ml, 100 mg/kg body weight) during the first eight postoperative days, and were sacrificed on day 28. Healing of the ureteral anastomosis and proliferation of urothelial cells was examined histologically and immunohistochemically. In vitro, a concentration of 10 ng/mm2 paclitaxel can be considered as non-toxic, while still exerting an anti-proliferative effect on urothelial cells. Histologically, typical wound healing processes were seen at the site of the ureteral anastomosis in vivo. Proliferation of urothelial cells was significantly lower in animals with paclitaxel-coated stents compared to those with uncoated stents (LI 41.27 vs. 51.58, p < 0.001). Our results indicate that stenting of ureteral anastomoses with paclitaxel-coated stents can reduce hyperplastic proliferation of ureteral tissue. Paclitaxel-coated stents thus might be able to prevent not only scar-induced postoperative stenosis after reconstructive surgery, but also hyperplastic urothelial reaction in non-anastomotic stent patients as part of their inflammatory response to the foreign material.


Assuntos
Stents Farmacológicos , Paclitaxel/administração & dosagem , Ureter/efeitos dos fármacos , Obstrução Ureteral/terapia , Urotélio/efeitos dos fármacos , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Humanos , Hiperplasia/prevenção & controle , Masculino , Ratos , Ureter/patologia , Ureter/cirurgia , Urotélio/citologia , Urotélio/patologia
8.
J Cardiothorac Surg ; 14(1): 216, 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31831023

RESUMO

BACKGROUND: Early neointimal hyperplasia of vein graft may be ameliorated via enhancing intravenous surface shear stress. Cellular processes including proliferation, apoptosis and migration of endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) may play very important roles in the process of neointimal hyperplasia of vein graft; and mitogen-activated protein kinase (MAPK) pathways including extracellular signal-regulated kinase (ERK1/2) and p38 pathways play vital roles in regulating a large variety of cellular processes. This study evaluated the impacts of shear stress and MAPK pathways on cellular processes of ECs in a co-culture system with VSMCs, and aimed to test the hypothesis that high shear stress suppresses proliferation and migration but promotes apoptosis of ECs co-cultured with VSMCs via down-regulating MAPK pathway. METHODS: Primary ECs and VSMCs derived from porcine great saphenous vein were collected, respectively. 4-7 generation of cells were used as work cells. ECs and VSMCs were co-cultured and synchronized under high and low shear stress using Parallel-Plate Flow Chamber system. And then, ECs co-cultured with VSMCs were incubated with U0126 (ERK1/2 inhibitor) or PD98059 (p38 inhibitor) under different shear stress. Proliferation, apoptosis and migration of ECs in a co-culture system with VSMCs were detected by 4,5-dimethyl-2-thiazolyl (MTT) assay and bromodeoxyuridine (BrdU) assay, fluorescent-activated cell sorting (FACS) technique, and Transwell assay separately. Each test repeated 3 times. Additionally, protein expressions of ERK1/2 and p38 MAPK were detected by using Western blot, respectively. RESULTS: Under higher level of shear stress condition, proliferation and migration of ECs co-cultured with VSMCs were suppressed, while cell apoptosis was promoted. And blocking ERK1/2 pathway by U0126 or blocking p38 pathway by PD98059, proliferation and migration of ECs co-cultured with VSMCs were further suppressed, while cell apoptosis was further promoted. Additionally, protein expressions of phosphorylation of ERK1/2 and p38MAPK were decreased under higher level of shear stress condition, and were further reduced by blocking ERK1/2 or p38 pathway under shear stress condition. CONCLUSIONS: High shear stress may suppress proliferation and apoptosis of ECs in a co-culture system with VSMCs but promote cell migration via down-regulating ERK1/2 and p38 MAPK pathways.


Assuntos
Células Endoteliais/citologia , Hiperplasia/prevenção & controle , Músculo Liso Vascular/citologia , Resistência ao Cisalhamento , Transplantes , Animais , Apoptose , Butadienos/farmacologia , Movimento Celular , Proliferação de Células , Células Cultivadas , Técnicas de Cocultura , Regulação para Baixo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Modelos Animais , Nitrilos/farmacologia , Veia Safena/citologia , Suínos
9.
Sci Rep ; 9(1): 16183, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31700015

RESUMO

Coronary artery bypass grafting is among the most commonly performed of all cardiovascular surgical procedures. However, graft failure due to stenosis reduces the long-term benefit of the intervention. This study asks if elevating plasma high density lipoprotein cholesterol (HDL-C) levels by inhibition of cholesteryl ester transfer protein (CETP) activity with des-fluoro-anacetrapib, an analog of the CETP inhibitor anacetrapib, prevents vein bypass-induced neointimal hyperplasia. NZW rabbits were placed on a normal chow diet or chow containing 0.14% (wt/wt) des-fluoro-anacetrapib for 6 weeks. Bypass grafting of the jugular vein to the common carotid artery was performed 2 weeks after starting dietary des-fluoro-anacetrapib supplementation. The animals were euthanised 4 weeks post-bypass grafting. Relative to control, dietary supplementation with des-fluoro-anacetrapib reduced plasma CETP activity by 89 ± 6.9%, increased plasma apolipoprotein A-I levels by 24 ± 5.5%, increased plasma HDL-C levels by 93 ± 26% and reduced intimal hyperplasia in the grafted vein by 38 ± 6.2%. Des-fluoro-anacetrapib treatment was also associated with decreased bypass grafting-induced endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), endothelial dysfunction, and smooth muscle cell (SMC) proliferation in the grafted vein. In conclusion, increasing HDL-C levels by inhibiting CETP activity is associated with inhibition of intimal hyperplasia in grafted veins, reduced inflammatory responses, improved endothelial function, and decreased SMC proliferation.


Assuntos
Anticolesterolemiantes/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Neointima/prevenção & controle , Oxazolidinonas/farmacologia , Animais , HDL-Colesterol/sangue , Hiperplasia/sangue , Hiperplasia/patologia , Hiperplasia/prevenção & controle , Molécula 1 de Adesão Intercelular/sangue , Masculino , Neointima/sangue , Neointima/patologia , Coelhos , Molécula 1 de Adesão de Célula Vascular/sangue
10.
Khirurgiia (Mosk) ; (10): 75-81, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31626243

RESUMO

Postoperative complications in vascular surgery may be partly provoked by suture material. Analysis of the mechanisms of these complications may be useful for their prevention. Mechanisms of suture-induced thrombosis and neointimal hyperplasia, possible strategies for prevention of postoperative complications including those allowing drug deliveries directly to the vascular anastomosis area are discussed in the article. According to the literature data, heparin is the most optimal drug for modifying suture material and prevention of thrombosis and neointimal hyperplasia. Heparin delivery to the vascular anastomosis site will reduce the risk of thrombosis by inhibiting the activity of thrombin. Complex of heparin and antithrombin III increases inhibitory effect of antithrombin against thrombin. In addition, heparin is able to reduce proliferation of vascular smooth muscle cells through inhibition of the synthesis of extracellular matrix proteases involved in migration and proliferation of cells. Thus, heparin delivery to the vascular injury site may be used to prevent thrombosis and myoproliferative response. Moreover, this strategy prevents complications associated with systemic administration of anticoagulants.


Assuntos
Suturas/efeitos adversos , Trombose/prevenção & controle , Doenças Vasculares/prevenção & controle , Procedimentos Cirúrgicos Vasculares/efeitos adversos , Anticoagulantes/administração & dosagem , Heparina/administração & dosagem , Humanos , Hiperplasia/etiologia , Hiperplasia/patologia , Hiperplasia/prevenção & controle , Neointima/patologia , Trombose/etiologia , Doenças Vasculares/etiologia
11.
Thromb Haemost ; 119(12): 2014-2024, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31634957

RESUMO

Inflammatory processes contribute to intimal hyperplasia (IH) and long-term failure of vein grafts used in bypass surgery. Leukocyte recruitment on endothelial cells of vessels during inflammation is regulated by P-selectin and P-selectin glycoprotein ligand-1 (PSGL-1), which also mediates the interaction between platelets and endothelial cells in vein grafts transferred to arteries. However, how this pathway causes IH in vein grafts is unclear. In this study, we used a murine model of vein grafting to investigate P-selectin-mediated platelet adhesion, followed by IH. On the luminal surface of the vein graft, leukocyte recruitment occurred mainly in areas with adhered platelets rather than on endothelial cells without adherent platelets 1 hour after vein grafting. Blockage of either P-selectin or PSGL-1 reduced platelet adhesion and leukocyte recruitment on the luminal surface of vein grafts. Inhibition of the P-selectin pathway in vein grafts significantly reduced platelet-mediated leukocyte recruitment and IH of vein grafts 28 days after surgery. The study demonstrates that functional blockage of the P-selectin/PSGL-1 pathway in the early inflammatory phase after vein grafting reduced leukocyte invasion in the vein graft wall and later IH development. The findings imply an attractive early time window for prevention of vein graft failure by manipulating platelet adhesion.


Assuntos
Hiperplasia/prevenção & controle , Glicoproteínas de Membrana/sangue , Selectina-P/sangue , Adesividade Plaquetária , Túnica Íntima/patologia , Veias/transplante , Animais , Plaquetas/patologia , Modelos Animais de Doenças , Células Endoteliais , Feminino , Inflamação , Leucócitos/metabolismo , Ligantes , Macrófagos/metabolismo , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos C57BL , Selectina-P/antagonistas & inibidores
12.
Peptides ; 121: 170131, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31408662

RESUMO

Extensive proliferation of vascular smooth muscle cell (VSMC) contributes to intimal hyperplasia following vascular injury, in which endoplasmic reticulum stress (ERS) plays a critical role. Intermedin (IMD) is a vascular paracrine/autocrine peptide exerting numerous beneficial effects in cardiovascular diseases. IMD overexpression could alleviate intimal hyperplasia. Here, we investigated whether endogenous IMD protects against intimal hyperplasia by inhibiting endoplasmic reticulum stress. The mouse left common carotid-artery ligation-injury model was established to induce intimal hyperplasia using IMD-/-mice and C57BL/6 J wild-type (WT) mice. Platelet-derived growth factor-BB (PDGF-BB) was used to stimulate the proliferation of VSMC. IMD-/- mice displayed exacerbated intimal hyperplasia induced by complete ligation of the left carotid artery at 14 d and 28 d compared to WT mice. However, IMD-deficiency had no effect on blood pressure, plasma triglyceride, and fasting blood glucose levels in mice. Furthermore, VSMCs derived from IMD-/- mice showed increased cell proliferation and dramatically elevated levels of glucose regulated protein 78 (GRP78), activating transcription factor 4 (ATF4), ATF6 mRNA under PDGF-BB treatment compared to WT mice-derived VSMCs. In addition, exogenous administration of IMD significantly attenuated PDGF-BB-induced cell proliferation and GRP78, phosphorylase-inositol requiring enzyme 1α, ATF4, and ATF6 protein levels. Thus, endogenous IMD may counteract ERS to exert protective role in response to vascular injury and IMD is expected to be a therapeutic target for the prevention and treatment of restenosis.


Assuntos
Estresse do Retículo Endoplasmático/genética , Hiperplasia/genética , Miócitos de Músculo Liso/metabolismo , Neuropeptídeos/genética , Túnica Íntima/metabolismo , Fator 4 Ativador da Transcrição , Fator 6 Ativador da Transcrição/genética , Fator 6 Ativador da Transcrição/metabolismo , Animais , Becaplermina/farmacologia , Artérias Carótidas/cirurgia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Regulação da Expressão Gênica , Proteínas de Choque Térmico , Hiperplasia/metabolismo , Hiperplasia/patologia , Hiperplasia/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Neuropeptídeos/deficiência , Cultura Primária de Células , Transdução de Sinais , Túnica Íntima/patologia
13.
Lab Invest ; 99(12): 1861-1873, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31409891

RESUMO

Hypertrophic scars (HSs) are characterized by fibroblast hyperproliferation and excessive matrix deposition. During wound healing, transforming growth factor (TGF)-ß1/Smad signaling acts as a key regulator. As a transcriptional corepressor of TGF-ß1/Smads, SnoN is expressed at low levels in many fibrotic diseases due to TGF-ß1/Smad-induced degradation. SnoN residue (1-366; SR) is resistant to TGF-ß1-induced degradation. However, the expression and role of SR in HSs are unknown. Here, we inhibited TGF-ß1/Smad signaling via overexpression of SR to block fibroblast transdifferentiation, proliferation, and collagen deposition during HS formation. Our results showed that SnoN was downregulated in HS fibroblasts (HSFs) owing to TGF-ß1/Smad-induced degradation. Overexpression of SR in normal human dermal fibroblasts (NHDFs) and HSFs successfully blocked phosphorylation of Smad2 and Smad3, thereby inhibiting NHDF transdifferentiation and HSF proliferation and reducing type I collagen (ColI) and type III collagen (ColIII) production and secretion. In addition, we applied overexpressed full-length SnoN (SF) and SR to wound granulation tissue in a rabbit model of HSs. SR reduced wound scarring, improved collagen deposition and arrangement of scar tissue, and decreased mRNA and protein expression of ColI, ColIII, and α-smooth muscle actin (α-SMA) more effectively than SF in vivo. These results suggest that SR could be a promising therapy for the prevention of HS.


Assuntos
Cicatriz Hipertrófica/prevenção & controle , Fibroblastos/metabolismo , Terapia Genética , Peptídeos e Proteínas de Sinalização Intracelular/uso terapêutico , Proteínas Proto-Oncogênicas/uso terapêutico , Adolescente , Adulto , Animais , Cicatriz Hipertrófica/metabolismo , Matriz Extracelular/metabolismo , Feminino , Humanos , Hiperplasia/prevenção & controle , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lentivirus , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Coelhos , Distribuição Aleatória , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Ubiquitina/metabolismo , Adulto Jovem
14.
Cell Mol Biol (Noisy-le-grand) ; 65(5): 49-53, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31304906

RESUMO

The aim of the present study was to investigate the correlation between human papillomavirus (HPV) type 6/11 and 16/18 infections and glandular thickening mammary gland hyperplasia in order to explore methods for preventing glandular thickening mammary gland hyperplasia. A total of 240 patients with glandular thickening mammary gland hyperplasia who were treated by surgery in our hospital from January 2012 to June 2017 were enrolled in the present study. The hyperplastic breast tissue and adjacent normal breast tissue were taken to test HPV type 6/11 and 16/18 infections using conventional PCR and in situ hybridization techniques. The correlations between HPV type 6/11 and 16/18 infections and glandular thickening mammary gland hyperplasia were analyzed using statistical methods of chi-square test. The infection rates of HPV type 6/11 and 16/18 in the hyperplastic breast tissue were 31.95% and 34.91%, respectively and 11.83% and 14.79% in the normal breast tissue, respectively. The differences were statistically significant (all p<0.05). HPV type 6/11 and 16/18 infections may be closely related to the development of glandular thickening mammary gland hyperplasia, and may be one of the causes of glandular thickening mammary gland hyperplasia.


Assuntos
Papillomavirus Humano 11/genética , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/genética , Hiperplasia/virologia , Glândulas Mamárias Humanas/patologia , Infecções por Papillomavirus/patologia , Distribuição de Qui-Quadrado , DNA Viral/genética , Feminino , Humanos , Hiperplasia/prevenção & controle , Hiperplasia/cirurgia , Hibridização In Situ , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Globinas beta/genética
15.
Nutr Res ; 68: 34-44, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31306903

RESUMO

The polyherbal blend Zyflamend™ has been shown to have anti-inflammatory properties and attenuate inflammatory-modulated pathologies. Fish oils have also been shown to have cardioprotective properties. However, the beneficial effects of their combination have not been investigated. Intimal hyperplasia (IH), a pathological remodeling response of a vessel to injury, is heavily regulated by an immune-mediated reaction. The objective of this study was to determine if dietary supplementation with Zyflamend and/or Wholemega could affect inflammatory-dependent vascular remodeling mechanisms when provided at human equivalent doses. Based on their anti-inflammatory properties and protective benefits demonstrated in previous pre-clinical studies, we hypothesized administration of these supplements would prevent IH in an animal model of vascular injury. The diets of aged male rats were supplemented with human equivalent doses of Zyflamend (Zyf) and/or Wholemega (WMega) or placebo (Plac) for 1wk prior to balloon angioplasty (BA)-induced injury of the left carotid artery. At 28d post-injury morphometric analysis of carotid tissue revealed IH was decreased in Zyf + WMega animals compared to placebo, while Zyf or WMega independently had no significant effect. Serum cytokine screening indicated injury-induced interleukin family isoforms, interferon-γ, and macrophage inflammatory proteins were downregulated by Zyf + WMega. Immunohistochemical staining for monocyte/macrophage phenotypic markers revealed that while overall monocyte/macrophage vessel infiltration was not affected, Zyf + WMega limited the alternative differentiation of M2 macrophages and reduced the presence of myofibroblasts in the injured vessel wall. In summary, dietary supplementation with Zyf + WMega attenuated the acute inflammatory response following vascular injury and inhibited IH development in vivo.


Assuntos
Lesões das Artérias Carótidas/patologia , Artéria Carótida Primitiva/patologia , Óleos de Peixe/administração & dosagem , Extratos Vegetais/administração & dosagem , Angioplastia com Balão , Animais , Lesões das Artérias Carótidas/etiologia , Artéria Carótida Primitiva/química , Citocinas/sangue , Dieta , Suplementos Nutricionais , Feminino , Hiperplasia/prevenção & controle , Inflamação/sangue , Masculino , Placebos , Ratos , Ratos Sprague-Dawley
16.
Colloids Surf B Biointerfaces ; 180: 168-176, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31048242

RESUMO

Due to their relatively good biocompatibility and inactivity, titanium oxide films (Ti-O) are used in the coating of coronary stents, which reduces metal corrosion, slows metal ion release, and improves endothelial cell (EC) compatibility. Here, we report further functionalizing Ti-O with biological cues for selective endothelialization. Selenocystine with an l- or a d-enantiomer was first immobilized on the Ti-O film via polydopamine to generate nitric oxide (NO) endogenously, which inhibited smooth muscle cell (SMC) proliferation, followed by the grafting of a functional KREDVC peptide to induce EC adhesion. The synergistic effects of the immobilized KREDVC, surface chirality, and NO generation on selective endothelialization were investigated. The results showed that the surface chirality of the l-enantiomer and KREDVC grafting significantly enhanced the attachment and growth of ECs compared to SMCs. An in vivo study showed von Willebrand factor expression was increased and neointimal hyperplasia was significantly decreased in samples with l-selenocystine immobilization and KREDVC grafting. In summary, these findings provide new insights on the surface modification of cardiovascular implants with selective endothelialization.


Assuntos
Cistina/análogos & derivados , Hiperplasia/prevenção & controle , Indóis/química , Neointima/prevenção & controle , Oligopeptídeos/química , Compostos Organosselênicos/química , Polímeros/química , Titânio/química , Animais , Prótese Vascular/efeitos adversos , Implante de Prótese Vascular , Proliferação de Células/efeitos dos fármacos , Técnicas de Cocultura , Cistina/química , Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Hiperplasia/etiologia , Hiperplasia/metabolismo , Hiperplasia/patologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Neointima/etiologia , Neointima/metabolismo , Neointima/patologia , Óxido Nítrico/biossíntese , Óxido Nítrico/farmacologia , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Titânio/farmacologia , Fator de von Willebrand/genética , Fator de von Willebrand/metabolismo
17.
Dig Dis Sci ; 64(9): 2548-2554, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30937720

RESUMO

BACKGROUND: The colon is partly controlled by myenteric and submucosal plexuses, which respond to stress and lead to some gastrointestinal disorders. These plexuses play roles in irritable bowel syndrome. Patients suffering from this syndrome can be treated with some antidepressants, including sertraline and nortriptyline. AIMS: The primary aim of study was to compare the effect of a sertraline and a nortriptyline on the structural changes of the enteric neurons after stress exposure in both sexes. The secondary objectives were to evaluate the effects of stress on the submucosal and myenteric plexuses. METHODS: Male and female Sprague-Dawley rats were assigned to four subgroups. The first subgroup received no stress. The other three subgroups received chronic variable stress (CVS) and were given phosphate buffer, sertraline (10 mg/kg/day), or nortriptyline (10 mg/kg/day). After 45 days, the neuron number in their colon plexuses was estimated using the stereologic method. RESULTS: The number of neurons increased by 40-51% in the submucosal plexus and by 57-69% in the myenteric plexus in the CVS group compared with the control group (p < 0.002) without any sex preference. The increment was significantly higher in the myenteric plexus than in the submucosal plexus (p < 0.05). Moreover, co-treatment of stressed rats with sertraline and nortriptyline could prevent the cellular hyperplasia of the plexuses, with more effective action for sertraline (p < 0.02). CONCLUSIONS: Stress exposure for 45 days induced hyperplasia of the colon's enteric plexuses in both sexes. However, these drugs could prevent the changes, with a more effective action for sertraline.


Assuntos
Colo/inervação , Plexo Mientérico/patologia , Neurônios/patologia , Nortriptilina/uso terapêutico , Sertralina/uso terapêutico , Plexo Submucoso/patologia , Animais , Antidepressivos Tricíclicos/uso terapêutico , Feminino , Hiperplasia/etiologia , Hiperplasia/prevenção & controle , Masculino , Ratos , Ratos Sprague-Dawley , Inibidores de Captação de Serotonina/uso terapêutico , Estresse Fisiológico , Estresse Psicológico/complicações
18.
Life Sci ; 221: 72-82, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30738868

RESUMO

AIMS: The proliferation of VSMCs is the pathologic basis for intimal hyperplasia after angioplasty in diabetic patients. Translocator protein (TSPO), located in the outer mitochondrial membrane, has been found to regulate redox intermediate components in cell dysfunction. We hypothesized that TSPO may regulate VSMC proliferation and migration, and be involved in the intimal hyperplasia after angioplasty in diabetes. MATERIALS AND METHODS: Cell proliferation was measured by cell counting and MTT assays. Cell migration was measured by Transwell® and scratch-wound assays. TSPO expression in arteries of rats and high glucose-treated A10 cells were detected by immunoblotting and immunofluorescence staining. Neointimal formation of carotid artery was induced by balloon injury in type 2 diabetic rat. KEY FINDINGS: TSPO expression was increased in the arterial samples from diabetic rats and A10 cells treated with high glucose. Down-regulation of TSPO expression by siRNA decreased the high-glucose-induced VSMC proliferation and migration in A10 cells. This phenomenon could be simulated by using TSPO ligands, PK 11195 and Ro5-4864. cGMP/PKG signals were involved in the TSPO ligand action, since in the presence of cGMP or PKG inhibitor ODQ or KT5823 respectively, the effect of PK 11195 on VSMC proliferation was blocked. Furthermore, PK 11195 significantly inhibited neointimal formation by the inhibition of VSMC proliferation. SIGNIFICANCE: This study suggests that TSPO inhibition suppresses the proliferation and migration of VSMCs induced by hyperglycemia, consequently, preventing atherosclerosis and restenosis after angioplasty in diabetic conditions. TSPO may be a potential therapeutic target to reduce arterial remodeling induced by angioplasty in diabetes.


Assuntos
Proteínas de Transporte/metabolismo , Hiperplasia/metabolismo , Receptores de GABA-A/metabolismo , Animais , Benzodiazepinonas/farmacologia , Artérias Carótidas/patologia , Proteínas de Transporte/fisiologia , Movimento Celular , Proliferação de Células , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Modelos Animais de Doenças , Hiperplasia/prevenção & controle , Isoquinolinas/farmacologia , Ligantes , Masculino , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Neointima/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/fisiologia
19.
Heart Vessels ; 34(7): 1230-1239, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30671641

RESUMO

We established a rabbit iliac artery restenosis model to explore the impact of Telmisartan on the expression of Connexin43 (Cx43) and neointimal hyperplasia. Thirty New Zealand white rabbits were randomly divided into three groups: control group (n = 10), restenosis group (n = 10), and Telmisartan group (n = 10). The restenosis model was established by high-cholesterol diet combined with double-balloon injury of iliac arteries. In addition, Telmisartan at 5 mg/(kg day) was administered to the rabbits of Telmisartan group on the second day after the second balloon injury. All rabbits were killed at the end of the experiment followed by institution policy. Before sacrifice, blood samples were obtained to test serum angiotensinII (AngII). Iliac arteries were isolated for morphological analysis and determining the expression of Cx43 by HE staining, immunohistochemical analysis, reverse transcription-polymerase chain reaction (RT-PCR), and Western Blotting analysis. Then, the local AngII levels of arteries were measured by radioimmunoassay. As compared with controls, the expression of Cx43 mRNA (0.98 ± 0.08) vs. (1.27 ± 0.17), P < 0.01), and Cx43 protein [(0.75 ± 0.08) vs. (0.90 ± 0.08), P < 0.05] of restenosis group were increased, which were significantly higher than those of Telmisartan group [Cx43 mRNA: (1.27 ± 0.17) vs. (1.00 ± 0.20), P < 0.01; Cx43 protein: (0.90 ± 0.08) vs. (0.82 ± 0.05), P < 0.05]. Furthermore, The intima thickness [(266.12 ± 70.27) vs. (2.85 ± 0.19) µm, P < 0.01] and the local AngII [(115.6 ± 15.7) vs. (90.1 ± 7.7), P < 0.05] of restenosis group were raised when compared with controls. Telmisartan group exhibited thinner intima compared with restenosis group [(68.22 ± 24.37) vs. (266.12 ± 70.27), P < 0.01]. However, the local AngII levels between these two groups were approximate. In addition, the plasma concentration of AngII was not significantly different among three groups. In conclusion, Telmisartan can inhibit the expression of connexin43 and neointimal hyperplasia in iliac artery restenosis model.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Conexina 43/metabolismo , Artéria Ilíaca/lesões , Telmisartan/farmacologia , Animais , Cateterismo , Proliferação de Células/efeitos dos fármacos , Conexina 43/genética , Hiperplasia/prevenção & controle , Artéria Ilíaca/patologia , Masculino , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/citologia , Neointima/prevenção & controle , Coelhos
20.
IUBMB Life ; 71(5): 632-642, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30597731

RESUMO

Vascular smooth muscle cell (VSMC) hyperproliferation is the main pathological process in various cardiovascular diseases, such as vascular restenosis. This process may be repressed by RING finger protein 10 (RNF10) in metabolic syndrome (MetS) rats. The aim of this study is to evaluate the inhibitory effects and molecular mechanisms of RNF10 on VSMC hyperproliferation. Neointimal hyperplasia in MetS and high-glucose-induced VSMC hyperproliferation were measured after infection with adenoviruses encoding RNF10 (Ad-RNF10), short hairpin RNF10 (Ad-shRNF10), or green fluorescent protein (Ad-GFP). In vivo and in vitro, we found that overexpression of RNF10 significantly affected neointima formation and VSMC proliferation, and displayed further inhibitory activity by promoting mesenchyme homeobox 2 (Meox2) and suppressing activating protein 1 (AP-1). In contrast, Ad-shRNF10 had an opposite effect on neointimal hyperplasia and VSMC hyperproliferation in vivo and in vitro. Our study indicated that RNF10 inhibited the hyperproliferation with the activities of Meox2 and AP-1 proteins. RNF10 may be a next drug target for treating vascular restenosis and other related cardiovascular diseases. © 2018 IUBMB Life, 71(5):632-642, 2019.


Assuntos
Proteínas de Transporte/metabolismo , Proliferação de Células , Reestenose Coronária/prevenção & controle , Hiperplasia/prevenção & controle , Síndrome Metabólica/fisiopatologia , Músculo Liso Vascular/citologia , Neointima , Proteínas do Tecido Nervoso/metabolismo , Adenoviridae/fisiologia , Infecções por Adenoviridae/virologia , Angioplastia Coronária com Balão/efeitos adversos , Animais , Proteínas de Transporte/genética , Movimento Celular , Células Cultivadas , Reestenose Coronária/etiologia , Reestenose Coronária/patologia , Dieta Hiperlipídica/efeitos adversos , Hiperplasia/etiologia , Hiperplasia/patologia , Masculino , Síndrome Metabólica/etiologia , Músculo Liso Vascular/metabolismo , Proteínas do Tecido Nervoso/genética , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
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