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1.
EuroIntervention ; 12(6): 790-7, 2016 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-27542793

RESUMO

AIMS: Our aim was to evaluate arterial responses to paclitaxel and a novel fluorocopolymer-coated nitinol low-dose paclitaxel-eluting stent (FP-PES). METHODS AND RESULTS: Human smooth muscle cell (SMC) migration was assessed after exposure to paclitaxel in vitro. For pharmacokinetics and vascular response, FP-PES or bare metal stents (BMS) were implanted in porcine iliofemoral arteries. Paclitaxel significantly inhibited human coronary and femoral artery SMC migration at doses as low as 1 pM. Inhibition was significantly greater for femoral compared with coronary artery SMCs from 1 pM to 1 µM. Pharmacokinetics showed consistent paclitaxel release from FP-PES over the study duration. The peak arterial wall paclitaxel level was 3.7 ng/mg at 10 days, with levels decreasing to 50% of peak at 60 days and 10% at 180 days. Paclitaxel was not detected in blood or remote organs. Arteriogram and histomorphometry analyses showed FP-PES significantly inhibits neointimal proliferation versus BMS at 30 and 90 days. Re-endothelialisation scores were not different between groups. CONCLUSIONS: Paclitaxel affected femoral artery SMC migration at lower concentrations and to a greater degree than it did coronary artery SMCs. The novel FP-PES used in this preclinical study demonstrated a vascular healing response similar to BMS, while significantly inhibiting neointimal formation up to 90 days.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Stents Farmacológicos , Miócitos de Músculo Liso/efeitos dos fármacos , Paclitaxel/administração & dosagem , Ligas , Animais , Antineoplásicos Fitogênicos/farmacocinética , Movimento Celular/efeitos dos fármacos , Vasos Coronários/citologia , Artéria Femoral/citologia , Humanos , Modelos Animais , Neointima/prevenção & controle , Paclitaxel/farmacocinética , Polímeros , Suínos
2.
Coron Artery Dis ; 25(3): 198-207, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24642807

RESUMO

BACKGROUND: The utility of animal models for the prediction of drug-eluting stent (DES) efficacy in human clinical trials is still unclear. The familial hypercholesterolemic swine (FHS) model has been shown to induce a human-like neointimal response to bare metal stent (BMS) implantation. However, its utility to discriminate efficacy signals following DES implantation is unknown. In this study, we aimed to test the efficacy and healing response of several everolimus-eluting stent (EES) platforms in the coronary territory of the FHS. METHODS: A total of 19 EES platforms (SYNERGY=6, SYNERGY½-dose=7, and PROMUS Element=6) and an identical BMS control (Element=6) were implanted into the coronary arteries of nine FHS. All implants were performed under intravascular ultrasound guidance using a 1.2 : 1 overstretch ratio. At 30 days, the vascular response to the implant was evaluated by quantitative coronary angiography, optical coherence tomography, and histology. RESULTS: At 28 days, all EES platforms showed a significant decrease in angiographic late lumen loss (between 27 and 37%) compared with the BMS control group. This finding was confirmed both by optical coherence tomography (mean neointimal thickness=28-42% reduction) and by histology (mean neointimal thickness=44-55% reduction). All EES platforms showed similar degrees of neointimal inhibition. The presence of moderate to severe para-strut inflammation was observed in 83% of the stent sections in the BMS group compared with 28.6% in the SYNERGY½-dose group and 0% in the SYNERGY and PROMUS groups (P=0.0002). There was a 68-95% reduction in MMP9 expression in the media in all EES platforms compared with the BMS controls. The presence of mild to moderate para-strut fibrin deposits ranged from 66.7 to 83.4% in all EES platforms compared with 16.7% in the EBMS group. CONCLUSION: The FHS coronary injury model showed the efficacy of several EES platforms compared with an identical BMS control. Everolimus eluted from different polymeric platforms showed lower levels of inflammation and slightly higher fibrin deposits compared with BMS controls.


Assuntos
Vasos Coronários/patologia , Modelos Animais de Doenças , Stents Farmacológicos , Hiperlipoproteinemia Tipo II , Neointima , Sirolimo/análogos & derivados , Animais , Implante de Prótese Vascular/métodos , Angiografia Coronária/métodos , Stents Farmacológicos/efeitos adversos , Stents Farmacológicos/normas , Everolimo , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/terapia , Imunossupressores/farmacologia , Masculino , Modelos Cardiovasculares , Neointima/diagnóstico , Neointima/etiologia , Polímeros/farmacologia , Sirolimo/farmacologia , Suínos , Tomografia de Coerência Óptica/métodos , Resultado do Tratamento , Ultrassonografia de Intervenção/métodos
3.
J Cardiovasc Pharmacol ; 59(2): 165-74, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21983747

RESUMO

Everolimus, a pharmaceutical component of drug-eluting stents, inhibits coronary vessel restenosis, but the antirestenotic mechanisms of action remain unclear. Here, we describe the effects of everolimus on key contributors to vessel restenosis, smooth muscle cell proliferation, and migration. In a dose-dependent fashion, everolimus reduced human coronary artery smooth muscle cell (HCASMC) proliferation without toxicity in a bimodal fashion, with accentuated potency occurring at 10 µM. Everolimus arrested the majority of HCASMCs in G1-phase, whereas it reduced the fraction of cells in S-phase at doses that inhibited DNA synthesis (bromodeoxyuridine incorporation). Consistent with this, Western blotting demonstrated that everolimus reduced activation and expression of G1-phase cell cycle progression factors, including p70S6K and cyclin D, respectively, decreased levels of proliferating cell nuclear antigen, and attenuated growth factor/serum-induced phosphorylation of the cell cycle phase transition intermediate, retinoblastoma protein. Everolimus did not, however, affect HCASMC migration. These observations suggest that everolimus acts as an antiproliferative, but not antimigratory, compound to account for at least some of the clinical efficacy exhibited by this drug as an antirestenotic agent. Moreover, everolimus-induced inhibition of the mammalian target of rapamycin complex 1 and regulation of cyclin-mediated cell cycle progression actions likely account for the antiproliferative effects of this compound on HCASMCs.


Assuntos
Proliferação de Células/efeitos dos fármacos , Reestenose Coronária/prevenção & controle , Vasos Coronários/efeitos dos fármacos , Sirolimo/análogos & derivados , Western Blotting , Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Vasos Coronários/citologia , Vasos Coronários/metabolismo , Ciclina D/metabolismo , Relação Dose-Resposta a Droga , Everolimo , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/farmacologia , Alvo Mecanístico do Complexo 1 de Rapamicina , Complexos Multiproteicos , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Proteínas/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Sirolimo/administração & dosagem , Sirolimo/farmacologia , Serina-Treonina Quinases TOR
4.
Biomaterials ; 31(14): 3755-61, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20181394

RESUMO

The desire to reduce the strut thickness of cardiovascular stents has driven the development of a new high strength radiopaque alloy, based on additions of platinum to a chromium-rich iron based matrix. This paper reports on initial development of the alloy and the rationale for selection of the composition. Data is presented for tensile and microstructural characterization, surface oxide analysis, corrosion resistance and endothelial cell response of the alloy. The results demonstrate the solid solution strengthening effect of the platinum, with an average yield strength of 480 MPa achieved. The material surface consists of primarily chromium oxide which contributes to the high corrosion resistance observed. The cell assay result suggests that surfaces of this Pt-enhanced alloy endothelialize in a manner comparable to stainless steel.


Assuntos
Ligas/química , Sistema Cardiovascular , Aço/química , Stents , Ligas/análise , Proliferação de Células , Corrosão , Células Endoteliais/citologia , Humanos , Teste de Materiais , Oxigênio/análise , Espectroscopia Fotoeletrônica , Propriedades de Superfície , Temperatura , Resistência à Tração
5.
Circ Res ; 105(10): 1003-12, 2009 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-19797172

RESUMO

RATIONALE: Sirolimus-eluting coronary stents (SESs) and paclitaxel-eluting coronary stents (PESs) are used to reduce restenosis but have different sites of action. The molecular targets of sirolimus overlap with those of the peroxisome proliferator-activated receptor (PPAR)gamma agonist rosiglitazone (RSG) but the consequence of this interaction on endothelialization is unknown. OBJECTIVE: Using the New Zealand white rabbit iliac model of stenting, we examined the effects of RSG on SESs, PESs, and bare metal stents endothelialization. METHODS AND RESULTS: Animals receiving SESs, PESs, or bare metal stents and either RSG (3 mg/kg per day) or placebo were euthanized at 28 days, and arteries were evaluated by scanning electron microscopy. Fourteen-day organ culture and Western blotting of iliac arteries and tissue culture experiments were conducted. Endothelialization was significantly reduced by RSG in SESs but not in PESs or bare metal stents. Organ culture revealed reduced vascular endothelial growth factor in SESs receiving RSG compared to RSG animals receiving bare metal stent or PESs. Quantitative polymerase chain reaction in human aortic endothelial cells (HAECs) revealed that sirolimus (but not paclitaxel) inhibited RSG-induced vascular endothelial growth factor transcription. Western blotting demonstrated that inhibition of molecular signaling in SES+RSG-treated arteries was similar to findings in HAECs treated with RSG and small interfering RNA to PPARgamma, suggesting that sirolimus inhibits PPARgamma. Transfection of HAECs with mTOR (mammalian target of rapamycin) short hairpin RNA and with Akt2 small interfering RNA significantly inhibited RSG-mediated transcriptional upregulation of heme oxygenase-1, a PPARgamma target gene. Chromatin immunoprecipitation assay demonstrated sirolimus interferes with binding of PPARgamma to its response elements in heme oxygenase-1 promoter. CONCLUSIONS: mTOR/Akt2 is required for optimal PPARgamma activation. Patients who receive SESs during concomitant RSG treatment may be at risk for delayed stent healing.


Assuntos
Stents Farmacológicos , Hipoglicemiantes/farmacologia , Imunossupressores/farmacologia , PPAR gama/antagonistas & inibidores , Paclitaxel/farmacologia , Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sirolimo/farmacologia , Tiazolidinedionas/farmacologia , Moduladores de Tubulina/farmacologia , Animais , Aorta/metabolismo , Células Cultivadas , Células Endoteliais/metabolismo , Oclusão de Enxerto Vascular , Heme Oxigenase-1/biossíntese , Heme Oxigenase-1/genética , Humanos , Modelos Biológicos , PPAR gama/genética , PPAR gama/metabolismo , Proteínas Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Coelhos , Rosiglitazona , Serina-Treonina Quinases TOR
6.
Biochem Biophys Res Commun ; 330(1): 194-203, 2005 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-15781250

RESUMO

Cigarette smoke (CS)-induced emphysema is attributable to matrix metalloproteinase-12 (MMP-12) in mice, however, a relationship between CS and MMP-12 is absent in human emphysema. Here, we show that cigarette smoke condensate (CSC) induces MMP-12 gene expression in airway-like epithelia through a hydrogen peroxide (H(2)O(2))-dependent pathway involving NADPH oxidase, AP-1, and TNF-alpha. Cigarette smoke condensate-induced H(2)O(2) production and MMP-12 gene expression were inhibited by apocynin, a specific inhibitor of NADPH oxidases, while 3-aminobenzamide, an inhibitor of AP-1, attenuated CSC-induced MMP-12 gene expression. Messenger RNAs encoding phagocytic NADPH oxidase components and a homologue of p67phox, p51 (NOXA1), were detected, while mRNA of dual oxidase (Duox)1 was unchanged by CSC. Enbrel, an inhibitor of TNF-alpha function, reduced CSC-induced H(2)O(2) production and MMP-12 expression. These findings provide novel evidence of a direct relationship between CS exposure and MMP-12 in human airway epithelia and suggest several targets for modulation of this potentially pathogenic pathway.


Assuntos
Brônquios/enzimologia , Regulação da Expressão Gênica , Metaloendopeptidases/genética , Nicotiana , Fumaça , Sequência de Bases , Brônquios/citologia , Células Cultivadas , Primers do DNA , Ativação Enzimática , Epitélio/enzimologia , Humanos , Peróxido de Hidrogênio/metabolismo , Metaloproteinase 12 da Matriz , NADPH Oxidases/metabolismo , Reação em Cadeia da Polimerase , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Necrose Tumoral alfa/fisiologia
7.
Biochem Biophys Res Commun ; 324(2): 534-46, 2004 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-15474460

RESUMO

Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins, which may be responsible for enlargement of alveoli in chronic obstructive pulmonary disease (COPD) and remodeling of pulmonary tissue associated with chronic asthma. Here, we provide novel evidence that MMP-12 is expressed and secreted by normal human bronchial epithelial cell cultures (NHBECs) and reveal the regulation of MMP-12 gene expression by tumor necrosis factor-alpha (TNF-alpha), epidermal growth factor (EGF), and interferon gamma (IFN-gamma). Reverse transcription-polymerase chain reaction analyses demonstrated MMP-12 mRNA presence in unstimulated differentiated NHBEC cultures. Cultures stimulated independently with EGF or IFN-gamma failed to alter MMP-12 mRNA abundance, while TNF-alpha, TNF-alpha+EGF, or TNF-alpha+IFN-gamma elicited relatively early (6 h) peak increases in MMP-12 mRNA levels. Western blot analyses specifically indicated the presence of MMP-12 in differentiated NHBEC-conditioned media. These findings indicate that the bronchial epithelium may be an important source of elastolytic activity in COPD and tissue remodeling in chronic asthma.


Assuntos
Asma/metabolismo , Brônquios/citologia , Células Epiteliais/citologia , Metaloendopeptidases/metabolismo , Ar , Western Blotting , Caseínas/química , Células Cultivadas , Meios de Cultivo Condicionados/farmacologia , Células Epiteliais/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Humanos , Interferon gama/metabolismo , Metaloproteinase 12 da Matriz , Mucinas/metabolismo , Estrutura Terciária de Proteína , Doença Pulmonar Obstrutiva Crônica/metabolismo , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo
8.
J Exp Med ; 197(6): 703-9, 2003 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-12642602

RESUMO

Interleukin (IL)-13 has recently been shown to play important and unique roles in asthma, parasite immunity, and tumor recurrence. At least two distinct receptor components, IL-4 receptor (R)alpha and IL-13Ralpha1, mediate the diverse actions of IL-13. We have recently described an additional high affinity receptor for IL-13, IL-13Ralpha2, whose function in IL-13 signaling is unknown. To better appreciate the functional importance of IL-13Ralpha2, mice deficient in IL-13Ralpha2 were generated by gene targeting. Serum immunoglobulin E levels were increased in IL-13Ralpha2-/- mice despite the fact that serum IL-13 was absent and immune interferon gamma production increased compared with wild-type mice. IL-13Ralpha2-deficient mice display increased bone marrow macrophage progenitor frequency and decreased tissue macrophage nitric oxide and IL-12 production in response to lipopolysaccharide. These results are consistent with a phenotype of enhanced IL-13 responsiveness and demonstrate a role for endogenous IL-13 and IL-13Ralpha2 in regulating immune responses in wild-type mice.


Assuntos
Interleucina-13/metabolismo , Receptores de Interleucina/fisiologia , Animais , Células Cultivadas , Fibroblastos/citologia , Fibroblastos/fisiologia , Marcação de Genes , Imunoglobulinas/sangue , Interferon gama/sangue , Interleucina-13/imunologia , Subunidade alfa1 de Receptor de Interleucina-13 , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Interleucina/genética , Receptores de Interleucina/imunologia , Receptores de Interleucina-13 , Receptores de Interleucina-4/imunologia , Receptores de Interleucina-4/metabolismo , Fator de Transcrição STAT6 , Transdução de Sinais/fisiologia , Células-Tronco/imunologia , Células-Tronco/metabolismo , Transativadores/genética , Transativadores/metabolismo
9.
Microcirculation ; 9(2): 133-45, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11932780

RESUMO

OBJECTIVE: To evaluate the expression and regulation of a novel B7-like protein, PD-L1, the ligand for the immunoinhibitory receptor PD-1 expressed on activated T-cells, on microvascular endothelial cells (ECs) METHODS: PD-L1 expression on ECs in vitro and in vivo was quantified by using a dual radiolabeled antibody technique after treatment with interferons (IFN) and IL-12, respectively. Changes in the level of PD-L1 mRNA were determined by using RT-PCR. RESULTS: PD-L1 was observed to be present on ECs under basal conditions. Treatment of ECs with IFN-alpha, -beta and -gamma, but not LPS, was observed to induce elevations in the mRNA and surface expression of PD-L1 on ECs. By using a dual radiolabeled monoclonal antibody (mAb) technique, PD-L1 expression in various tissues of control and IL-12 challenged wild-type and IFN-gamma-deficient mice was measured. A significant increase in PD-L1 expression was observed in tissues at 24 hours after IL-12-challenge, with peak levels of PD-L1 occurring 72 hours after IL-12 challenge. IL-12 was not effective at inducing PD-L1 expression in tissues of IFN-gamma-deficient mice. CONCLUSIONS: These data show the expression of a novel B7-like molecule on murine ECs that is mediated by IFN-alpha, -beta, and -gamma, and suggest a potential pathway by which ECs may modulate T-cell function.


Assuntos
Antígeno B7-1 , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/metabolismo , Endotélio Vascular/imunologia , Peptídeos/genética , Peptídeos/metabolismo , Animais , Antígeno B7-H1 , Proteínas Sanguíneas/imunologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas In Vitro , Interferon gama/deficiência , Interferon gama/genética , Interferon gama/farmacologia , Interleucina-12/farmacologia , Lipopolissacarídeos/farmacologia , Ativação Linfocitária , Masculino , Glicoproteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microcirculação/efeitos dos fármacos , Microcirculação/imunologia , Microcirculação/metabolismo , Peptídeos/imunologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Recombinantes , Linfócitos T/imunologia
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