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1.
J Diabetes Complications ; 37(4): 108421, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36905721

RESUMO

AIMS: The aim of this study was to investigate the effects of pioglitazone on reactive oxygen species (ROS), expressions/activities of MMPs and TIMP-2, and VSMC proliferation and vascular reactivity in high glucose (HG)-induced human saphenous vein (HSV) grafts. METHODS: HSV grafts (n = 10) obtained from patients undergoing CABG were incubated with 30 mM glucose and/or 10 µM pioglitazone or 0.1 % DMSO for 24 h after endothelium removal. ROS levels were examined by chemiluminescence assay, MMP-2,-9,-14, TIMP-2, and α-SMA expression/activity was determined by gelatine zymography/immunohistochemistry. Vascular reactivity to potassium chloride, noradrenaline, serotonin, prostaglandin F2α and papaverine was assessed in HSVs. RESULTS: HG induced superoxide anion (SA) (123 %) and other ROS levels (159 %), up-regulated MMP-2 expression (180 %)/activity (79 %), MMP-14 expression (24 %) and MMP-9 activity while down-regulating TIMP-2 expression (27 %). HG elevated total MMP-2/TIMP-2 ratio (483 %) and MMP-14/TIMP-2 ratio (78 %). However, HG plus pioglitazone inhibited SA (30 %) and other ROS levels (29 %), down-regulated MMP-2 expression (76 %)/activity (83 %), MMP-14 expression (38 %) and MMP-9 activity, while reversing TIMP-2 expression (44 %). HG plus pioglitazone decreased total MMP-2/TIMP-2 ratio (91 %) and MMP-14/TIMP-2 ratio (59 %). HG impaired contractions to all agents but pioglitazone improved them. CONCLUSIONS: Pioglitazone may contribute to the prevention of restenosis and maintaining vascular function in HSV grafts of DM patients undergoing CABG.


Assuntos
Metaloproteinase 2 da Matriz , Metaloproteinase 9 da Matriz , Estresse Oxidativo , Pioglitazona , Veia Safena , Humanos , Glucose/farmacologia , Glucose/metabolismo , Metaloproteinase 14 da Matriz/efeitos dos fármacos , Metaloproteinase 14 da Matriz/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pioglitazona/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Veia Safena/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-1/farmacologia , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Inibidor Tecidual de Metaloproteinase-2/farmacologia , Inflamação/metabolismo
2.
Drug Des Devel Ther ; 13: 1791-1801, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31213768

RESUMO

Background: Cardiopulmonary bypass (CPB) applied during coronary artery bypass grafting (CABG), promotes inflammation, generation of reactive oxygen species (ROS) and up-regulation of matrix metalloproteinases (MMPs). All these complications may lead to contractile dysfunction, restenosis and early graft failure, restricting long-term efficacy of bypass grafts. Low-dose doxycycline is a potent MMP inhibitor and ROS scavenger. In this study, we aimed to investigate the effects of doxycycline on ROS generation, MMP regulation and contractile dysfunction induced by H2O2 in human saphenous vein (HSV) grafts. Methods: HSV grafts (n=7) were divided into four groups after removing endothelial layer by mechanical scratching and incubated with 10 µM H2O2 and/or 10 µM doxycycline for 16 hrs. Untreated segments served as control. Concentration-response curves to noradrenaline (NA), potassium chloride (KCl), serotonin (5-HT) and papaverine were performed. Superoxide anion and other ROS levels were determined by using lucigenin- and luminol-enhanced chemiluminescence assays, respectively. Expression/activity of gelatinases (MMP-2/MMP-9) was examined by gelatin zymography. MMP-13 expression was evaluated by immunostaining/immunoscoring. Results: H2O2 incubation increased superoxide anion and other ROS levels. Doxycycline prevented these increments. H2O2 suppressed contractile responses to NA, KCl and 5-HT. Doxycycline ameliorated contractions to NA and KCl but not to 5-HT. H2O2 or doxycycline did not altered relaxation to papaverine. MMP-2 and MMP-13 expression increased with H2O2, but doxycycline inhibited MMP-2 up-regulation/activation. Conclusion: Low-dose doxycycline may have beneficial effects on increased oxidative stress, MMP up-regulation/activation and contractile dysfunction in HSV grafts.


Assuntos
Antibacterianos/farmacologia , Doxiciclina/farmacologia , Peróxido de Hidrogênio/antagonistas & inibidores , Metaloproteinase 2 da Matriz/metabolismo , Veia Safena/efeitos dos fármacos , Antibacterianos/administração & dosagem , Relação Dose-Resposta a Droga , Doxiciclina/administração & dosagem , Humanos , Peróxido de Hidrogênio/farmacologia , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Veia Safena/metabolismo , Relação Estrutura-Atividade , Regulação para Cima/efeitos dos fármacos
3.
Folia Histochem Cytobiol ; 54(4): 171-180, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27966209

RESUMO

INTRODUCTION: Matrix metalloproteinase enzymes (MMPs) play important role in inflammation, malignant cell proliferation, invasion and angiogenesis by mediating extracellular matrix degradation. Doxycycline, a synthetic tetracycline, behaves as a MMP inhibitor at a subantimicrobial dose and inhibits tumor cell proliferation, invasion and angiogenesis. The aberrant activity of nuclear factor kappa B (NF-κB) causes activation of MMPs and thereby proliferation and invasion of cancer cells. The aim of this study was to investigate the effects of doxycycline on the expression of MMPs in lipopolysaccharide (LPS)-induced PC3 human prostate cancer cells and the possible role of NF-κB signaling. MATERIAL AND METHODS: PC3 cells were incubated with LPS (0.5 µg/mL) for 24 h in the presence or absence of doxycycline (5 µg/mL). The effects of LPS and doxycycline on the expressions of MMP-2, MMP-8, MMP-9, MMP-10, NF-κB/p65, IκB-α, p-IκB-α, IKK-ß were examined by Western blotting and immunohistochemistry in PC3 cells. Furthermore, relative proteinase activities of MMP-2 and MMP-9 were determined by gelatin zymography. RESULTS: LPS increased expression and activity of MMP-9 and expression of MMP-8, MMP-10, NF-κB /p65, p-IκB-α, IKK-ß and doxycycline down-regulated its effects with the exception of MMP-10 expression. The expression of MMP-2 and IκB-α was affected by neither LPS nor doxycycline. CONCLUSIONS: Our findings indicate that doxycycline inhibits the expression of various MMPs and NF-κB signaling may play a role in the regulation of MMPs expression in LPS-induced PC3 human prostate cancer cells.


Assuntos
Doxiciclina/farmacologia , Lipopolissacarídeos/farmacologia , Metaloproteinases da Matriz/biossíntese , NF-kappa B/antagonistas & inibidores , Neoplasias da Próstata/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Ativação Enzimática , Gelatinases/metabolismo , Humanos , Quinase I-kappa B/metabolismo , Imuno-Histoquímica , Masculino , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Invasividade Neoplásica , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo
4.
Drug Des Devel Ther ; 10: 1453-60, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27143852

RESUMO

BACKGROUND: Bisphosphonates, including zoledronate, target osteoclasts and are widely used in the treatment of osteoporosis and other bone resorption diseases, despite side effects that include damaging the stomach epithelium. Beneficial and adverse effects on other organ systems, including the cardiovascular system, have also been described and could impact on the use of bisphosphonates as therapeutic agents. Vascular smooth muscle cells (VSMCs) are major constituents of the normal vascular wall and have a key role in intimal thickening and atherosclerosis, in part by secreting MMPs that remodel the extracellular matrix and cleave cell surface proteins or secreted mediators. In this study, we investigated the effects of zoledronate on MMP expression. METHODS: Rat VSMCs were stimulated by PDGF (50 ng/mL) plus TNF-α (10 ng/mL) or left unstimulated for a further 24 hours in serum-free medium. In other series of experiments, cells were pre-treated either with SC-514 (50 µM) or with apocynin (20 nM) for 2 hours, then zoledronate (100 µM) was added into 2% fetal calf serum containing medium for 24 hours. RESULTS AND DISCUSSION: Using isolated rat VSMCs in culture, zoledronate (100 µM) increased MMP-9 and -13 mRNA expressions but inhibited MMP-2 expression. MMP-9 and MMP-13 up-regulation was shown to depend on the NF-κB pathway; and this was activated by zoledronate. Furthermore, zoledronate elevated the levels of reactive oxygen species detected by either dichlorofluorescein in isolated VSMCs or lucigenin enhanced chemiluminescence in rat aortic rings in vitro. Apocynin, an inhibitor of NADPH oxidase, reversed NF-κB activation and MMP-9 and MMP-13 up-regulation by zoledronate. CONCLUSION: We conclude that zoledronate increases MMP-9 and MMP-13 expressions in rat VSMCs dependent upon stimulation of the NF-κB pathway by reactive oxygen species. Effects on MMP expression may contribute to the pharmacologic profile of bisphosphonates.


Assuntos
Difosfonatos/farmacologia , Imidazóis/farmacologia , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Animais , Células Cultivadas , Masculino , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Músculo Liso Vascular/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Ácido Zoledrônico
5.
J Cancer ; 6(10): 1020-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26366216

RESUMO

Discoidin Domain Receptors (DDR1/DDR2) are tyrosine kinase receptors which are activated by collagen. DDR signalling regulates cell migration, proliferation, apoptosis and matrix metalloproteinase (MMP) production. MMPs degrade extracellular matrix (ECM) and play essential role in tumor growth, invasion and metastasis. Nitrogen-containing bisphosphonates (N-BPs) which strongly inhibit osteoclastic activity are commonly used for osteoporosis treatment. They also have MMP inhibitory effect. In this study, we aimed to investigate the effects of zoledronate in PC3 cells and the possible role of DDR signalling and downstream pathways in these inhibitory effects. We studied messenger RNA (mRNA) and protein expressions of MMP-2,-9,-8, DDR1/DDR2 type I procollagen (TIP) and mRNA levels of PCA-1, MMP-13 and DDR-initiated signalling pathway players including K-Ras oncogene, ERK1, JNK1, p38, AKT-1 and BCLX in PC3 cells in the presence or absence of zoledronate (10-100 µM) for 2-3 days. Zoledronate (100 µM) down-regulated DDR1/ DDR2, TIP mRNAs but did not change MMP-13 (collagenase-3) mRNA. However, zoledronate up-regulated MMP-8 (collagenase-2) mRNA. Zoledronate also inhibited mRNA expressions of K-Ras, ERK1, AKT-1, BCLX and PCA-1; but did not change JNK1, p38 mRNA levels. Zoledronate (100 µM) supressed DDR1/DDR2, TIP expressions; and gelatinase (MMP-2/MMP-9) expressions/activities. Conversely, zoledronate up-regulated MMP-8 expression in PC3 cells. Zoledronate down-regulates MMP-2/-9 expressions in PC3 prostate cancer cells. DDR1/DDR2 signalling and DDR-initiated downstream Ras/Raf/ERK and PI3K/AKT pathways may at least partially responsible for MMP inhibitory effect of zoledronate.

6.
Exp Ther Med ; 8(6): 1695-1700, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25371717

RESUMO

Prostate cancer is the second leading cause of morbidity and mortality in males in the Western world. In the present study, LNCaP, which is an androgen receptor-positive and androgen-responsive prostate cancer cell line derived from lymph node metastasis, and DU145, which is an androgen receptor-negative prostate cancer cell line derived from brain metastasis, were investigated. TNFα treatment decreased p105 and p50 expression and R1881 treatment slightly decreased p105 expression but increased p50 expression with or without TNFα induction. As an aggressive prostate cancer cell line, DU145 transfected with six transmembrane protein of prostate (STAMP)1 or STAMP2 was also exposed to TNFα. Western blotting indicated that transfection with either STAMP gene caused a significant increase in NFκB expression following TNFα induction. In addition, following the treatment of LNCaP cells with TNFα, reverse transcription quantitative polymerase chain reaction (RT-qPCR) was performed with a panel of apoptosis-related gene primers. The apoptosis-related genes p53, p73, caspase 7 and caspase 9 showed statistically significant increases in expression levels while the expression levels of MDM2 and STAMP1 decreased following TNFα induction. Furthermore, LNCaP cells were transfected with a small interfering NFκB (siNFκB) construct for 1 and 4 days and induced with TNFα for the final 24 h. RT-qPCR amplifications were performed with apoptosis-related gene primers, including p53, caspases and STAMPs. However, no changes in the level of STAMP2 were observed between cells in the presence or absence of TNFα induction or between those transfected or not transfected with siNFκB; however, the level of STAMP1 was significantly decreased by TNFα induction, and significantly increased with siNFκB transfection. Silencing of the survival gene NFκB caused anti-apoptotic STAMP1 expression to increase, which repressed p53, together with MDM2. NFκB silencing had varying effects on a panel of cancer regulatory genes. Therefore, the effective inhibition of NFκB may be critical in providing a targeted pathway for prostate cancer prevention.

7.
Eur J Pharmacol ; 706(1-3): 98-106, 2013 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-23500209

RESUMO

Matrix metalloproteinase enzymes (MMPs) activated by oxidative stress are involved in the pathogenesis of cardiovascular diseases. Glutathione (GSH) plays an important protective role against oxidatively induced damage in mammalian tissues. We investigated the possible role of gelatinases and the effect of the semiessential amino acid 2-aminoethanesulfonic acid (taurine) in oxidatively induced damage by GSH depletion in rabbit cardiac tissues. Rabbits were treated with buthionine sulfoximine (BSO), an effective GSH-depleting compound. BSO treatment significantly reduced GSH and increased MDA (malondialdehyde) levels. BSO treatment caused significant increase in proMMP-2 levels. MMP-9 (pro and active) expressions were not found in either treated- or untreated heart tissues. TIMP-1(endogenous inhibitor of MMP-9) and MT-MMP1 (endogenous activator of MMP-2) were not affected by BSO. Immunoscoring showed that MMP-2 expression significantly increased in hearts from BSO treated group but MMP-9 antibody did not show any significant positive immunostaining from all groups. Type I procollagen and total collagen did not significantly alter in heart tissues from all treatment groups. Taurine restored the increased MDA and the diminished GSH levels by BSO treatment. Pro MMP-2 expression was prevented by taurine. These results suggest that MMP-2 is a major gelanitase in rabbit hearts under oxidative stress and pharmacological inhibition of MMP-2 activation by taurine could represent a useful strategy for the prevention and/or treatment of different cardiovascular disorders.


Assuntos
Metaloproteinase 2 da Matriz/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Taurina/farmacologia , Animais , Colágeno Tipo I/metabolismo , Feminino , Glutationa/deficiência , Masculino , Metaloproteinase 14 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Coelhos , Inibidor Tecidual de Metaloproteinase-1/metabolismo
8.
J Surg Res ; 182(1): 176-84, 2013 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-22981741

RESUMO

BACKGROUND: Acute renal failure due to renal ischemia/reperfusion (IR) injury is a significant clinical problem in cardiovascular surgery. Reactive oxygen species and inflammation play essential roles in the pathophysiology of IR injury. Matrix metalloproteinases (MMPs) are enzymes that play important roles in inflammation and mediate extracellular matrix degradation. It is known that peroxisome proliferator-activated receptor-γ agonists have antiinflammatory and antioxidant effects. In the present study, we aimed to investigate the effects of pioglitazone, a synthetic peroxisome proliferator-activated receptor-γ agonist, on MMPs and oxidative stress in a renal IR injury model in rats. MATERIALS AND METHODS: Male Wistar albino rats were divided into three groups: control (n = 7), placebo (n = 7; saline/p.o.), and pioglitazone (n = 7; 5 mg/kg/day/p.o.). In the control group, a right nephrectomy was conducted without left renal IR injury. In the placebo and pioglitazone groups, pretreatments were started 3 d before operation. In both groups, left renal pedicles were clamped for 60 min and then reperfused for 60 min. Paraffinized renal sections were evaluated histopathologically. Furthermore, expressions of MMP-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-2, superoxide dismutase 1 (SOD1), and p47-phox/p67-phox subunits of NADPH oxidase were determined by immunostaining and scoring. RESULTS: In the placebo group, renal IR injury induced diffuse tubular necrosis and intense acute inflammation, but pioglitazone inhibited these effects. MMP-2, MMP-9, and TIMP-2 expression increased in the placebo group. However, while MMP-2 and -9 expression decreased, TIMP-2 expression did not change in the pioglitazone group. p47-phox/p67-phox expression increased in the placebo group, but SOD1 expression did not change. Pioglitazone diminished p47-phox/p67-phox expression, whereas it enhanced SOD1 expression. CONCLUSION: Our results suggest that pioglitazone might be helpful to reduce renal IR injury because of its antiinflammatory and antioxidant effects.


Assuntos
Antioxidantes/uso terapêutico , Rim/irrigação sanguínea , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/agonistas , Traumatismo por Reperfusão/prevenção & controle , Tiazolidinedionas/farmacologia , Tiazolidinedionas/uso terapêutico , Animais , Antioxidantes/farmacologia , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Modelos Animais , NADPH Oxidases/metabolismo , Estresse Oxidativo/fisiologia , Fosfoproteínas/metabolismo , Pioglitazona , Ratos , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1 , Inibidor Tecidual de Metaloproteinase-2/metabolismo
9.
J Cardiothorac Surg ; 7: 57, 2012 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-22716287

RESUMO

BACKGROUND: Neointimal hyperplasia involving smooth muscle cell (SMC) proliferation, migration and extracellular matrix (ECM) degradation is an important component of atherosclerosis. It develops as a response to vascular injury after balloon angioplasty and vascular graft placement. Matrix metalloproteinases (MMPs) induce SMC proliferation, migration and contribute to intimal hyperplasia by degrading ECM. PPARγ agonists inhibit SMC proliferation, migration and lesion formation. In this study, we aimed to investigate the effects of PPARγ agonist rosiglitazone on neointimal hyperplasia and gelatinase (MMP-2 and MMP-9) expressions in rabbit carotid anastomosis model. METHODS: New Zealand white rabbits (n = 13, 2.7-3.2 kg) were divided into placebo and treatment groups. Right carotid artery (CA) was transected and both ends were anastomosed. Treatment group (n = 6) received rosiglitazone (3 mg/kg/day/p.o.) and placebo group (n = 7) received PBS (phosphate buffered saline, 2.5 ml/kg/day/p.o.) for 4 weeks postoperatively. After the sacrification, right and left CAs were isolated. Morphometric analyses and immunohistochemical examinations for gelatinases were performed. RESULTS: Intimal area (0.055 ± 0.005 control vs 0.291 ± 0.020 µm(2) anastomosed, p < 0,05) and index (0.117 ± 0.002 control vs 0.574 ± 0.013 anastomosed, p < 0,01) significantly increased in anastomosed arteries compared to control arteries from placebo group. However, in rosiglitazone-treated group, intimal area (0.291 ± 0.020 PBS vs 0.143 ± 0.027 rosiglitazone, p < 0,05) and index (0.574 ± 0.013 PBS vs 0.263 ± 0.0078 rosiglitazone, p < 0,01) significantly decreased. Furthermore, gelatinase immunopositivity was found to have significantly increased in anastomosed arteries from placebo group and decreased with rosiglitazone treatment. CONCLUSIONS: These results suggest that rosiglitazone may prevent neointimal hyperplasia, which is the most important factor involved in late graft failure, by inhibiting gelatinase enzyme expression.


Assuntos
Anastomose Cirúrgica/métodos , Artérias Carótidas/cirurgia , Neointima/patologia , Neointima/terapia , PPAR gama/agonistas , Tiazolidinedionas/farmacologia , Análise de Variância , Animais , Procedimentos Cirúrgicos Cardíacos , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/patologia , Distribuição de Qui-Quadrado , Feminino , Hiperplasia , Imuno-Histoquímica , Masculino , Metaloproteinases da Matriz/metabolismo , Neointima/tratamento farmacológico , Neointima/prevenção & controle , Coelhos , Rosiglitazona , Estatísticas não Paramétricas
10.
Br J Pharmacol ; 163(8): 1679-90, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21371008

RESUMO

BACKGROUND AND PURPOSE Matrix metalloproteinase (MMP) production from monocyte/macrophages is implicated in matrix remodelling and modulation of inflammation. However, knowledge of the patterns and mechanisms of gene regulation of MMPs and their endogenous tissue inhibitors (TIMPs) is fragmentary. MMP up-regulation may be a target for cyclooxygenase (COX) and prostaglandin (PG) receptor inhibition, but the extent and mechanisms of COX-independent MMP up-regulation are unclear. EXPERIMENTAL APPROACH We studied MMP mRNA expression and selected protein levels in human peripheral blood monocytes before and after adhesion, upon stimulation with bacterial lipopolysaccharide (LPS), PGE(2) or forskolin and after culturing with monocyte colony-stimulating factor on plastic or human fibronectin for up to 7 days. KEY RESULTS Monocyte adherence for 2 h transiently up-regulated COX-2, MMP-1, MMP-7 and MMP-10 mRNAs, and persistently up-regulated MMP-2, MMP-9, MMP-14 and MMP-19 mRNAs. LPS, PGE(2) or forskolin selectively increased MMP-1, MMP-9, MMP-10, MMP-12 and MMP-14 mRNAs. LPS increased PGE(2) production through COX but up-regulated MMP levels independently of COX. Differential dependence on inhibition of p42/44 and p38 mitogen-activated protein kinases, c-jun N-terminal kinase and inhibitor of κB kinase2 paralleled the diverse patterns of MMP stimulation by LPS. Differentiation on plastic increased mRNA levels of MMP-7, MMP-9, MMP-12 and MMP-14 and TIMP-2 and TIMP-3 independently of COX; fibronectin accelerated MMP but not TIMP up-regulation. CONCLUSIONS AND IMPLICATIONS Adhesion, LPS stimulation and maturation of human monocytes lead to selective, COX-independent MMP and TIMP gene regulation, which is a potential target for selective inhibition by signalling kinase inhibitors.


Assuntos
Adesão Celular/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Metaloproteases/fisiologia , Monócitos/metabolismo , Prostaglandina-Endoperóxido Sintases/genética , Colforsina/farmacologia , Dinoprostona/metabolismo , Fibronectinas/fisiologia , Humanos , Inflamação/fisiopatologia , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Lipopolissacarídeos/metabolismo , Monócitos/enzimologia , Subunidade p52 de NF-kappa B/antagonistas & inibidores , Subunidade p52 de NF-kappa B/genética , Subunidade p52 de NF-kappa B/metabolismo , Fitoterapia , Preparações de Plantas/farmacologia , Plásticos/metabolismo , Prostaglandina-Endoperóxido Sintases/biossíntese , Prostaglandina-Endoperóxido Sintases/metabolismo , RNA Mensageiro/análise , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Inibidores Teciduais de Metaloproteinases/biossíntese , Inibidores Teciduais de Metaloproteinases/genética , Regulação para Cima/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
11.
Anadolu Kardiyol Derg ; 11(2): 93-100, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21285021

RESUMO

OBJECTIVE: The aim of the present study was to investigate the effect of zoledronic acid (ZA), as a matrix metalloproteinase inhibitor, on neointimal hyperplasia in rabbit carotid anastomosis model. METHODS: New Zealand male rabbits were divided into two groups as placebo and treatment groups in this experimental study. After anesthesia, the right carotid artery of each rabbit was end-to-end anastomosed with an 8/0 polypropylene suture. Left carotid artery was kept as control without any operation. Placebo group (n=6) received phosphate buffered saline (PBS) (0.5mL/kg/day/s.c.) for 28 days postoperatively, whereas ZA group (n=6) received ZA (100 µg/kg/day/s.c.) for the same period. After sacrification, the anastomosed and control arteries were isolated. Morphometric and immunohistochemical examinations were performed. Statistical analyses of morphometric and immunohistochemical data were performed using two-way ANOVA and Chi-square test respectively. RESULTS: In PBS group, vascular injury in the anastomosed artery significantly increased the intimal area (anastomosed: 112.51±61.18 µm(2)*1000 vs. control: 22.62±4.26 µm(2)*1000, p<0.01) and intima/media index (anastomosed: 0.347±0.29 vs. control: 0.075±0.01, p<0.05) compared to control artery. ZA significantly reduced the intimal area (39.29±18.21 µm(2)*1000 , p<0.01) and intima/media index (0.112±0.07, p<0.05) compared to PBS group. Additionally, α-smooth muscle actin immunopositivity was found significantly decreased in anastomosed arteries from ZA group (ZA: 2.33±0.52 vs. PBS: 3.50±0.5, p<0.05). Moreover, intensive gelatinase (MMP-2 and MMP-9) immunoreactivities were clearly seen in anastomosed arteries compared to control arteries from PBS group. ZA apparently decreased immunopositivities for gelatinases in anastomosed arteries. CONCLUSION: ZA might be a promising agent for prevention of neointimal hyperplasia, which is the most significant cause of graft failures in late postoperative period.


Assuntos
Artérias Carótidas/cirurgia , Difosfonatos/uso terapêutico , Imidazóis/uso terapêutico , Inibidores de Metaloproteinases de Matriz , Neointima/prevenção & controle , Actinas/análise , Anastomose Cirúrgica , Animais , Artérias Carótidas/patologia , Difosfonatos/farmacologia , Modelos Animais de Doenças , Hiperplasia/tratamento farmacológico , Hiperplasia/prevenção & controle , Imidazóis/farmacologia , Imuno-Histoquímica , Masculino , Metaloproteinase 2 da Matriz/análise , Metaloproteinase 9 da Matriz/análise , Metaloproteinases da Matriz/análise , Músculo Liso Vascular/química , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/patologia , Neointima/tratamento farmacológico , Neointima/patologia , Coelhos , Distribuição Aleatória , Ácido Zoledrônico
12.
J Cardiovasc Pharmacol Ther ; 14(4): 292-301, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19734325

RESUMO

Matrix metalloproteinases (MMPs), and, in particular, gelatinases (MMP-2 and MMP-9), have been implicated in vascular cell proliferation and/or migration, contributing to intimal thickening, an essential stage in the development of atherosclerosis and restenosis following balloon angioplasty. Endothelin, a strong chemoatractant and mitogen, has been shown to promote smooth muscle cell proliferation and migration by activating MMPs via endothelin-A (ETA) receptors. The positioning of a soft silicon collar around the left carotid artery in rabbits results in intimal thickening. In this study, we investigate the possible role of gelatinases and the effect of a nonselective ETA/ETB receptor antagonist, TAK-044 (5 mg/kg body weight/day, subcutaneously [sc]), on these enzymes. Our results demonstrated that both MMP-2 and MMP-9 activities increased in response to collaring in placebo group, while treatment with TAK-044 significantly suppressed both gelatinase activities and proMMP-2 levels, and inhibited intimal thickening in collared arteries. These results suggest that either enhanced MMP expression or endothelin receptor antagonism may be involved in the formation of intimal thickening in this model.


Assuntos
Doença da Artéria Coronariana/metabolismo , Antagonistas dos Receptores de Endotelina , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Peptídeos Cíclicos/farmacologia , Animais , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/enzimologia , Doença da Artéria Coronariana/enzimologia , Doença da Artéria Coronariana/etiologia , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Precursores Enzimáticos/metabolismo , Feminino , Gelatinases/metabolismo , Masculino , Coelhos , Túnica Íntima/anatomia & histologia , Túnica Íntima/citologia , Túnica Íntima/efeitos dos fármacos , Túnica Íntima/metabolismo
13.
J Pharm Pharmacol ; 57(12): 1599-608, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16354404

RESUMO

Intimal thickening, due to smooth muscle cell migration and proliferation, is considered to be one of the major components of vascular proliferative disorders such as atherosclerosis and restenosis. One experimental model, resulting in intimal thickening in the rabbit, involves placing a silicon collar around the carotid artery, and is used in this study. Endothelin is known to act as a strong mitogen and to stimulate smooth muscle cell proliferation and migration. We investigated the contribution of endothelin to the development of collar-induced intimal thickening and the effects of TAK-044, (5 mg kg(-1) daily, s.c.), a non-selective ET(A)/ET(B) receptor antagonist, on intimal thickening and vascular reactivity changes in the collared rabbit carotid artery. Endothelin levels and the intimal cross-sectional area, as well as the ratio of intimal area to media (index), increased significantly in collared arteries as compared with those in sham-operated arteries. TAK-044 significantly inhibited intimal thickening and also decreased the index without affecting increased endothelin levels in collared arteries. Vascular reactivity changes in response to collaring produced predictable effects, such as decreased contractile responses to vasoconstrictor agents and increased sensitivity to serotonin (5-hydroxytryptamine, 5-HT). In terms of contractile responses in this model, TAK-044, in particular, did not affect collar-induced vascular reactivity changes. These results suggest that endothelin may be involved in the pathogenesis of collar-induced intimal thickening. As an endothelin receptor antagonist, TAK-044 may potentially be beneficial in the treatment of atherosclerosis.


Assuntos
Vasos Sanguíneos/patologia , Receptores de Endotelina/agonistas , Túnica Íntima/patologia , Animais , Pressão Sanguínea , Peso Corporal , Endotelina-1/sangue , Endotelina-1/fisiologia , Feminino , Imuno-Histoquímica , Antígeno Ki-67/metabolismo , Masculino , Coelhos
14.
Acta Cardiol ; 60(5): 493-9, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16261780

RESUMO

OBJECTIVE: Calcium channel blockers (CCBs) are among the most frequently prescribed cardiovascular drugs. It has been shown that these drugs have antiatherosclerotic effects in both experimental and clinical settings. However, calcium channel blockers have markedly different chemical structures and different effects on the cardiovascular system. We investigated the effect of CD-832, a Ca(+2) channel antagonist, on collar-induced intimal thickening, as well as accompanied reactivity changes in rabbit carotid artery. METHODS AND RESULTS: Rabbits received 5 mg/kg/day CD-832 or vehicle (polyethylene glycol, 0.5 ml/kg/day) intramuscularly for a week before and 2 weeks after the collar application. Histological and isometric force measurements were performed in segments from sham and collared carotid arteries. A three-week treatment with CD-832 did not inhibit the intimal thickening caused by perivascular application of a silicone collar. Potassium chloride (KCl), phenylephrine, 5-hydroxytryptamine (5-HT, serotonin) and histamine induced concentration-dependent contractions in both sham-operated (sham) and collared arteries. Collar-induced attenuations in maximum KCl, histamine, phenylephrine and 5-HT contractions were not affected by CD-832. Collaring caused an increase in pD2 values of 5-HT and a decrease in those of phenylephrine, histamine and acetylcholine. CD-832 did not affect the altered sensitivity to these agonists. CONCLUSIONS: These results demonstrate that, in rabbit carotid artery, CD-832 did not inhibit the collar-induced intimal thickening and did not affect the accompanying changes in vascular reactivity.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Artéria Carótida Primitiva/efeitos dos fármacos , Niacinamida/análogos & derivados , Nifedipino/análogos & derivados , Túnica Íntima/efeitos dos fármacos , Acetilcolina/farmacologia , Agonistas alfa-Adrenérgicos/farmacologia , Animais , Artéria Carótida Primitiva/patologia , Artéria Carótida Primitiva/fisiopatologia , Endotélio Vascular/efeitos dos fármacos , Feminino , Histamínicos/farmacologia , Masculino , Modelos Animais , Modelos Cardiovasculares , Niacinamida/farmacologia , Nifedipino/farmacologia , Fenilefrina/farmacologia , Cloreto de Potássio/farmacologia , Coelhos , Serotonina/farmacologia , Serotoninérgicos/farmacologia , Túnica Íntima/patologia , Túnica Íntima/fisiopatologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
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