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1.
Open Heart ; 3(1): e000342, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26848395

RESUMEN

OBJECTIVE: The balance between coronary endothelial dysfunction and repair is influenced by many protective and deleterious factors circulating in the blood. We studied the relationship between oxidised low-density lipoprotein (oxLDL), circulating endothelial progenitor cells (EPCs) and coronary endothelial function in patients with stable coronary heart disease (CHD). METHODS: 33 patients with stable CHD were studied. Plasma oxLDL was measured using ELISA, coronary endothelial function was assessed using intracoronary acetylcholine infusion and EPCs were quantified using flow cytometry for CD34(+)/KDR(+) cells. RESULTS: Plasma oxLDL correlated positively with the number of EPCs in the blood (r=0.46, p=0.02). There was a positive correlation between the number of circulating EPCs and coronary endothelial function (r=0.42, p=0.04). There was no significant correlation between oxLDL and coronary endothelial function. CONCLUSIONS: Plasma levels of oxLDL are associated with increased circulating EPCs in the blood of patients with CHD, which may reflect a host-repair response to endothelial injury. Patients with stable CHD had a high prevalence of coronary endothelial dysfunction, which was associated with lower numbers of circulating EPCs, suggesting a mechanistic link between endothelial dysfunction and the pathogenesis of atherosclerosis.

2.
Anal Biochem ; 499: 71-77, 2016 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-26820096

RESUMEN

Resistance arteries have been implicated as a major contributing factor in the sequela of disease conditions such as hypertension and diabetes and, as such, are a major focus of cardiovascular research. The paracrine influence of the intimal endothelial layer of resistance arteries is well established. Considering the growing body of evidence substantiating a functionally relevant vascular adventitia, in this study we have established a technique that permits determination of the functional influence of the adventitial layer on resistance artery tone. Isolating adventitial-dependent function, analogous to isolating endothelial function, has potentially significant implications for studying the as yet unexplored role of the microvascular adventitial layer in modulating acute vascular contractile function.


Asunto(s)
Técnicas de Ablación , Adventicia/fisiología , Adventicia/cirugía , Microcirculación , Vasoconstricción , Animales , Endotelio Vascular/fisiología , Endotelio Vascular/cirugía , Masculino , Ratas , Ratas Sprague-Dawley
3.
PeerJ ; 3: e1192, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26312183

RESUMEN

Objective. Emerging evidence suggests an important role for mast cells in vein graft failure. This study addressed the hypothesis that perivascular mast cells regulate in situ vascular inflammatory and proliferative responses and subsequent vein graft neointimal lesion formation, using an optimized local mast cell reconstitution method. Methods and Results. Neointimal hyperplasia was induced by insertion of a vein graft into the right carotid artery in wild type and mast cell deficient Kit(W-sh/W-sh) mice. In some experiments, mast cells were reconstituted systemically (tail vein injection of bone marrow-derived mast cells) or locally (directly into the right neck area) prior to vein grafting. Vein graft neointimal lesion formation was significantly (P < 0.05) reduced in Kit(W-sh/W-sh) mice. Mast cell deficiency reduced the number of proliferating cells, and inhibited L-selectin, CCL2, M-CSF and MIP-3α expression in the vein grafts. Local but not systemic mast cell reconstitution restored a perivascular mast cell population that subsequently promoted neointimal formation in mast cell deficient mice. Conclusion. Our data demonstrate that perivascular mast cells play a key role in promoting neointima formation by inducing local acute inflammatory and proliferative responses. These results suggest that ex vivo intraoperative targeting of mast cells may have therapeutic potential for the prevention of pathological vein graft remodeling.

4.
Am J Physiol Lung Cell Mol Physiol ; 309(4): L333-47, 2015 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-26024891

RESUMEN

The p38 mitogen-activated protein kinase (MAPK) system is increasingly recognized as an important inflammatory pathway in systemic vascular disease but its role in pulmonary vascular disease is unclear. Previous in vitro studies suggest p38 MAPKα is critical in the proliferation of pulmonary artery fibroblasts, an important step in the pathogenesis of pulmonary vascular remodeling (PVremod). In this study the role of the p38 MAPK pathway was investigated in both in vitro and in vivo models of pulmonary hypertension and human disease. Pharmacological inhibition of p38 MAPKα in both chronic hypoxic and monocrotaline rodent models of pulmonary hypertension prevented and reversed the pulmonary hypertensive phenotype. Furthermore, with the use of a novel and clinically available p38 MAPKα antagonist, reversal of pulmonary hypertension was obtained in both experimental models. Increased expression of phosphorylated p38 MAPK and p38 MAPKα was observed in the pulmonary vasculature from patients with idiopathic pulmonary arterial hypertension, suggesting a role for activation of this pathway in the PVremod A reduction of IL-6 levels in serum and lung tissue was found in the drug-treated animals, suggesting a potential mechanism for this reversal in PVremod. This study suggests that the p38 MAPK and the α-isoform plays a pathogenic role in both human disease and rodent models of pulmonary hypertension potentially mediated through IL-6. Selective inhibition of this pathway may provide a novel therapeutic approach that targets both remodeling and inflammatory pathways in pulmonary vascular disease.


Asunto(s)
Antiinflamatorios/farmacología , Hipertensión Pulmonar/tratamiento farmacológico , Imidazoles/farmacología , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Arteria Pulmonar/fisiopatología , Piridinas/farmacología , Remodelación Vascular/efectos de los fármacos , Animales , Hipoxia de la Célula , Proliferación Celular , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/enzimología , Fibroblastos/metabolismo , Humanos , Hipertensión Pulmonar/enzimología , Hipertensión Pulmonar/fisiopatología , Interleucina-6/metabolismo , Masculino , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/patología , Ratas Sprague-Dawley
5.
Vascul Pharmacol ; 71: 108-15, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25866325

RESUMEN

Creation of an autologous arteriovenous fistula (AVF) for vascular access in haemodialysis is the modality of choice. However neointimal hyperplasia and loss of the luminal compartment result in AVF patency rates of ~60% at 12months. The exact cause of neointimal hyperplasia in the AVF is poorly understood. Vascular trauma has long been associated with hyperplasia. With this in mind in our rabbit model of AVF we simulated cannulation autologous to that undertaken in vascular access procedures and observed significant neointimal hyperplasia as a direct consequence of cannulation. The neointimal hyperplasia was completely inhibited by topical transdermal delivery of the non-steroidal anti-inflammatory (NSAID) diclofenac. In addition to the well documented anti-inflammatory properties we have identified novel anti-proliferative mechanisms demonstrating diclofenac increases AMPK-dependent signalling and reduced expression of the cell cycle protein cyclin D1. In summary prophylactic transdermal delivery of diclofenac to the sight of AVF cannulation prevents adverse neointimal hyperplasic remodelling and potentially offers a novel treatment option that may help prolong AVF patency and flow rates.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Fístula Arteriovenosa/prevención & control , Cateterismo/efectos adversos , Diclofenaco/administración & dosificación , Neointima/tratamiento farmacológico , Grado de Desobstrucción Vascular/efectos de los fármacos , Administración Cutánea , Animales , Fístula Arteriovenosa/enzimología , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Células Cultivadas , Relación Dosis-Respuesta a Droga , Sistemas de Liberación de Medicamentos/métodos , Activación Enzimática/efectos de los fármacos , Activación Enzimática/fisiología , Hiperplasia/enzimología , Hiperplasia/prevención & control , Neointima/enzimología , Conejos , Grado de Desobstrucción Vascular/fisiología
6.
Pharmacol Ther ; 138(1): 53-65, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23333349

RESUMEN

Mast cells are increasingly being recognized as effector cells in many cardiovascular conditions. Many mast-cell-derived products such as tryptase and chymase can, through their enzymic action, have detrimental effects on blood vessel structure while mast cell-derived mediators such as cytokines and chemokines can perpetuate vascular inflammation. Mice lacking mast cells have been developed and these are providing an insight into how mast cells are involved in cardiovascular diseases and, as knowledge increase, mast cells may become a viable therapeutic target to slow progression of cardiovascular disease.


Asunto(s)
Mastocitos/metabolismo , Enfermedades Vasculares/metabolismo , Animales , Humanos , Hiperplasia/metabolismo , Trasplante de Tejidos/efectos adversos , Venas/trasplante
7.
Catheter Cardiovasc Interv ; 81(4): 698-708, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22581717

RESUMEN

OBJECTIVE: The aim of this study was to assess the efficacy of stent-based delivery of succinobucol alone and in combination with rapamycin in a porcine coronary model. BACKGROUND: Current drugs and polymers used to coat coronary stents remain suboptimal in terms of long term efficacy and safety. Succinobucol is a novel derivative of probucol with improved antioxidant and anti-inflammatory properties. METHODS: Polymer-free Yukon stents were coated with 1% succinobucol (SucES), 2% rapamycin (RES), or 1% succinobucol plus 2% rapamycin solutions (SucRES) and compared with a bare metal stent (BMS). RESULTS: The in vivo release profile of SucES indicated drug release up to 28 days (60% drug released at 7 days); 41 stents (BMS, n = 11; SucES, n =10; RES, n = 10; SucRES, n = 10) were implanted in the coronary arteries of 17 pigs. After 28 days, mean neointimal thickness was 0.31 ± 0.14 mm for BMS, 0.51 ± 0.14 mm for SucES, 0.19 ± 0.11 mm for RES, and 0.36 ± 0.17 mm for SucRES (P < 0.05 for SucES vs. BMS). SucES increased inflammation and fibrin deposition compared with BMS (P < 0.05), whereas RES reduced inflammation compared with BMS (P < 0.05). CONCLUSION: In this model, stent-based delivery of 1% succinobucol using a polymer-free stent platform increased neointimal formation and inflammation following coronary stenting.


Asunto(s)
Fármacos Cardiovasculares/toxicidad , Vasos Coronarios/efectos de los fármacos , Stents Liberadores de Fármacos , Inflamación/inducido químicamente , Intervención Coronaria Percutánea/instrumentación , Probucol/análogos & derivados , Animales , Fármacos Cardiovasculares/administración & dosificación , Fármacos Cardiovasculares/farmacocinética , Bovinos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Vasos Coronarios/metabolismo , Vasos Coronarios/patología , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Células Endoteliales/efectos de los fármacos , Células Endoteliales/patología , Fibrina/metabolismo , Inflamación/patología , Masculino , Metales , Modelos Animales , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/patología , Neointima , Intervención Coronaria Percutánea/efectos adversos , Probucol/administración & dosificación , Probucol/farmacocinética , Probucol/toxicidad , Diseño de Prótesis , Sirolimus/administración & dosificación , Porcinos
8.
Thromb Res ; 130(2): 210-5, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22520023

RESUMEN

BACKGROUND: The effect of reactive oxygen species (ROS) on platelet function in coronary heart disease (CHD) is complex and poorly defined. Platelet aggregation studies in healthy volunteers have demonstrated contrasting results when platelets are exposed to ROS. We investigated the effect of ROS on whole blood aggregation (WBA) and the endothelial cell-platelet interaction in patients with CHD. METHODS AND RESULTS: ROS generated by xanthine and xanthine oxidase caused a concentration-dependent inhibition of WBA in blood from healthy donors and patients with CHD. In patients with CHD, 100 µM xanthine and 100 mU/ml xanthine oxidase inhibited WBA in response to 3 µg/ml collagen by 28.9% (95% CI 15.9%-41.8%, p<0.001) and in response to 5 µM ADP by 36.0% (95% CI 9.6%-62.4%, p=0.005). Using nitrotyrosine expression, platelets isolated from patients with CHD were found to be susceptible to peroxynitrite damage. The addition of 1 × 10(5) cultured endothelial cells inhibited WBA in response to 3 µg/ml collagen by 31.2% (95% CI 12.2%-50.2%, p<0.05) and in response to 5 µM ADP by 31.6% (95% CI 2.5-60.7%, p<0.05). Addition of xanthine and xanthine oxidase did not alter this effect, however pre-treatment of endothelial cells with a nitric oxide synthase inhibitor (L-NAME) partly reversed the inhibition. CONCLUSION: ROS inhibit WBA in blood from patients with CHD. Whilst endothelial cells also inhibit WBA, the effect is attenuated by L-NAME, suggesting that nitric oxide is likely to remain an important protective mechanism against thrombosis in CHD.


Asunto(s)
Plaquetas/citología , Enfermedad Coronaria/metabolismo , Células Endoteliales/citología , Endotelio Vascular/citología , Agregación Plaquetaria , Especies Reactivas de Oxígeno/metabolismo , Anciano , Plaquetas/metabolismo , Comunicación Celular/efectos de los fármacos , Enfermedad Coronaria/sangre , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Inhibidores Enzimáticos/farmacología , Femenino , Hemostasis/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , NG-Nitroarginina Metil Éster/farmacología , Agregación Plaquetaria/efectos de los fármacos , Tirosina/análogos & derivados , Tirosina/metabolismo , Xantina/metabolismo , Xantina Oxidasa/metabolismo
9.
Am J Respir Cell Mol Biol ; 47(2): 140-8, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22383583

RESUMEN

Hypoxic pulmonary hypertension is a worldwide public health problem. Statins attenuate hypoxic pulmonary hypertension in animal models, but the mechanism of action and applicability of these results to human treatment are not established. In hypoxic models, pulmonary artery fibroblast proliferation contributes substantially to pulmonary vascular remodeling. We previously showed that acute hypoxic pulmonary adventitial fibroblast proliferation can be selectively inhibited by statins and p38 mitogen-activated protein (MAP) kinase inhibitors. Here we used complementary chronic hypoxic and acute hypoxic coculture models to obtain necessary preclinical information regarding the utility of fluvastatin in the treatment of chronic hypoxic pulmonary hypertension. The effects of fluvastatin, cholesterol pathway intermediates, and related inhibitors on hypoxic adventitial fibroblast proliferation, p38 MAP kinase phosphorylation, and pulmonary artery smooth muscle cell proliferation were determined, using complementary chronic hypoxic rat and acute hypoxic bovine cell models. Fluvastatin reversed the proliferative phenotypic switch in adventitial fibroblasts from chronic hypoxic animals. This effect was circulation-specific, and implicated a Rac1-p38 MAP kinase signaling pathway. Coculture and conditioned media experiments also implicated this statin-sensitive signaling pathway in the release of pulmonary artery smooth muscle cell mitogens by hypoxic pulmonary adventitial fibroblasts. Treprostinil, sildenafil, and bosentan exerted no effect on the hypoxic fibroblast phenotype. Phenotypic changes (increased proliferation and mitogen release) in pulmonary artery fibroblasts during chronic hypoxia are dependent on a Rac1-p38 MAP kinase signaling pathway. The inhibition of these phenotypic changes with fluvastatin may be therapeutically relevant in high-altitude residents and in patients with hypoxic lung disease.


Asunto(s)
Ácidos Grasos Monoinsaturados/farmacología , Fibroblastos/efectos de los fármacos , Hipertensión Pulmonar/tratamiento farmacológico , Hipoxia/tratamiento farmacológico , Indoles/farmacología , Animales , Bovinos , Hipoxia de la Célula/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Colesterol/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patología , Fluvastatina , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Hipoxia/metabolismo , Hipoxia/patología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/fisiopatología , Masculino , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Fenotipo , Fosforilación/efectos de los fármacos , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
10.
Eur J Pharm Biopharm ; 80(3): 578-84, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22227367

RESUMEN

The present study is an attempt to leverage therapeutic benefits of curcumin in pulmonary hypertension by encapsulating it in biodegradable poly(lactide-co-glycolic) acid nanoparticles. Pulmonary hypertension is induced in experimental animals by subjecting them to chronic hypoxic conditions. The ability of curcumin encapsulated nanoparticles to manage pulmonary hypertension is measured by right ventricular hypertrophy, haematocrit, vascular remodelling and target tissue levels of curcumin. Further, single oral dose tissue distribution of the nanoparticulate curcumin was also assessed under normoxic and hypoxic conditions. Orally administered nanoparticulate curcumin failed to offer any protection against hypoxia induced pulmonary hypertension as indicated by insignificant changes in right ventricular hypertrophy and vascular remodelling that are similar to untreated groups. A significant difference in the target tissue levels was observed between normoxic vs. hypoxic rats. The study suggests that hypoxia has a major role in the particle localization in lungs probably due to the altered blood flow, increased barrier properties of the lung vasculature and decreased endocytosis. The target tissue levels of curcumin under hypoxia are much lower to that achieved in normoxic rats probably due to difference in particle dynamics, resulting in the failure of treatment.


Asunto(s)
Curcumina/administración & dosificación , Curcumina/farmacocinética , Hipertensión Pulmonar/tratamiento farmacológico , Hipoxia/tratamiento farmacológico , Nanopartículas/administración & dosificación , Administración Oral , Animales , Curcumina/química , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/metabolismo , Hipertrofia Ventricular Derecha/tratamiento farmacológico , Hipertrofia Ventricular Derecha/metabolismo , Hipoxia/inducido químicamente , Hipoxia/metabolismo , Ácido Láctico/química , Pulmón/irrigación sanguínea , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Masculino , Nanopartículas/química , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Arteria Pulmonar/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Distribución Tisular
11.
Toxicol In Vitro ; 25(8): 1680-6, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21782928

RESUMEN

Peroxynitrite is widely reported as highly cytotoxic; yet recent evidence indicates that at certain concentrations, it can induce pulmonary cell hyper-proliferation and tissue remodelling. This study aimed to establish the threshold concentration of peroxynitrite to induce functional impairment of bovine pulmonary artery endothelial (PAEC) and smooth muscle cells (PASMC). PAEC or PASMC were exposed to solution of peroxynitrite or 3-morpholinosydnonimine (SIN-1). Twenty-four hour cell viability, DNA synthesis, and protein biochemistry were assessed by trypan blue dye exclusion, [3H] thymidine incorporation and western blot analysis, respectively. Threshold concentration of peroxynitrite to significantly impair viability of PAEC and PASMC was 2 µM peroxynitrite. In PASMC and PAEC, low concentrations of peroxynitrite (2 nM-0.2 µM) increased cell proliferation and did not activate p38 MAP kinase. The decrease in DNA synthesis and cell viability caused by 2 µM peroxynitrite was associated with caspase-3 cleavage but not p38 activation. Also, 2-20 µM peroxynitrite significantly activated poly ADP ribose polymerase and stress activated kinase JNK in PAEC. However, the higher concentration of 20 µM peroxynitrite did cause a threefold increase in p38 activation. In conclusion, the threshold for the cytotoxic effects of peroxynitrite was 2 µM; which caused apoptotic cell death independent of p38 MAP kinase activation in pulmonary artery cells.


Asunto(s)
Células Endoteliales/efectos de los fármacos , Molsidomina/análogos & derivados , Miocitos del Músculo Liso/efectos de los fármacos , Donantes de Óxido Nítrico/toxicidad , Oxidantes/toxicidad , Ácido Peroxinitroso/toxicidad , Animales , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Bovinos , Células Endoteliales/metabolismo , Endotelio Vascular/citología , Endotelio Vascular/metabolismo , L-Lactato Deshidrogenasa/metabolismo , MAP Quinasa Quinasa 4/metabolismo , Molsidomina/toxicidad , Miocitos del Músculo Liso/metabolismo , Necrosis/inducido químicamente , Necrosis/metabolismo , Poli(ADP-Ribosa) Polimerasas/metabolismo , Arteria Pulmonar/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
12.
J Cardiovasc Pharmacol ; 57(5): 584-8, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21326106

RESUMEN

There is separate evidence for peroxynitrite formation and hypoxia-induced cell proliferation in several models of hypoxic pulmonary hypertension. We therefore hypothesized that the stimulation of pulmonary artery smooth muscle cells (PASMCs) proliferation by hypoxia is due to peroxynitrite formation. The effect of hypoxia alone and in combination with ≤ 0.2 µM peroxynitrite on PASMCs was investigated in explants from bovine lungs grown in 1%, 5%, or 10% oxygen for 24 hours with or without peroxynitrite. At 0.1% fetal bovine serum, DNA synthesis of PASMCs (assessed by 3H thymidine incorporation) was increased by transient exposure to 0.2 µM peroxynitrite (by 158% ± 14%, P < 0.01) or to 24 hours of hypoxia (5% oxygen) (by 221% ± 17%, P < 0.01). Results were similar at 2.5% fetal bovine serum. Treatment of PASMCs with 0.2 µM peroxynitrite or 5% O2 hypoxia caused a significant increase in nitrotyrosine formation to a similar extent and intensity. The proliferative response to 0.2 µM peroxynitrite or to the combination of peroxynitrite plus 5% O2 was similar to the effect of 5% O2 alone and was abolished by simultaneous treatment with peroxynitrite scavenger-ebselen (5 µM). Our present data indicate that hypoxia can initiate peroxynitrite-induced proliferative events and suggest a mechanism for the vascular hypertrophy associated with pulmonary hypertension.


Asunto(s)
Proliferación Celular , Células Endoteliales/patología , Hipoxia/patología , Músculo Liso Vascular/patología , Ácido Peroxinitroso/metabolismo , Arteria Pulmonar/patología , Enfermedad Aguda , Animales , Azoles/farmacología , Bovinos , Técnicas de Cultivo de Célula , Hipoxia de la Célula , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Depuradores de Radicales Libres/farmacología , Hipoxia/metabolismo , Isoindoles , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Compuestos de Organoselenio/farmacología , Oxígeno/metabolismo , Arteria Pulmonar/metabolismo
13.
J Vasc Res ; 48(2): 141-9, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-20938206

RESUMEN

BACKGROUND: Grafting veins into the arterial circulation causes endothelial damage and neointimal hyperplasia. However, the remodelling of vein grafts and the contribution of the endothelium is not well understood. Since nitric oxide (NO) has a crucial role in vascular function, we investigated the importance of NO synthases (NOSs) in vein graft re-endothelialization and remodelling in this study. METHODS AND RESULTS: Mouse isogenic vena cava was grafted into the carotid artery. Progressive remodelling of the grafted veins was evidenced by re-endothelialization at 2 weeks and subsequent appearance of vasomotor function at 4 weeks. Pharmacological inhibition of inducible NOS (iNOS) with the specific inhibitor 1400W, administered between 2 and 4 weeks after grafting, when re-endothelialization was complete, resulted in neoadventitial inflammation, neoadventitial thickening and impaired functional remodelling. CONCLUSION: Completion of re-endothelialization is pivotal in vein graft remodelling in the mouse and is associated with a series of changes in inflammation, proliferation and initiation of vascular functional remodelling. After re-endothelialization, iNOS upregulation may be an important mechanism to prevent secondary neoadventitial inflammation and preserve ongoing functional remodelling. iNOS activity could therefore be beneficial for long-term patency of the vein graft.


Asunto(s)
Arterias Carótidas/fisiología , Arterias Carótidas/cirugía , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Vena Cava Inferior/fisiología , Vena Cava Inferior/trasplante , Animales , Arterias Carótidas/trasplante , Tejido Conectivo/enzimología , Tejido Conectivo/inmunología , Endotelio Vascular/enzimología , Endotelio Vascular/fisiología , Inhibidores Enzimáticos/farmacología , Iminas/farmacología , Inflamación/enzimología , Masculino , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico Sintasa de Tipo II/metabolismo , Trasplantes , Túnica Íntima/patología , Regulación hacia Arriba , Injerto Vascular , Vena Cava Inferior/enzimología
14.
Eur J Pharmacol ; 650(1): 371-7, 2011 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-20950600

RESUMEN

Reduced NO levels due to the deficiency of tetrahydrobiopterin (BH(4)) contribute to impaired vasodilation in pulmonary hypertension. Due to the chemically unstable nature of BH(4), it was hypothesised that oxidatively stable analogues of BH(4) would be able to support NO synthesis to improve endothelial dysfunction in pulmonary hypertension. Two analogues of BH(4), namely 6-hydroxymethyl pterin (HMP) and 6-acetyl-7,7-dimethyl-7,8-dihydropterin (ADDP), were evaluated for vasodilator activity on precontracted rat pulmonary artery rings. ADDP was administered to pulmonary hypertensive rats, followed by measurement of pulmonary vascular resistance in perfused lungs and eNOS expression by immunohistochemistry. ADDP and HMP caused significant relaxation in vitro in rat pulmonary arteries depleted of BH(4) with a maximum relaxation at 0.3µM (both P<0.05). Vasodilator activity of ADDP and HMP was completely abolished following preincubation with the NO synthase inhibitor, L-NAME. ADDP and HMP did not alter relaxation induced by carbachol or spermine NONOate. BH(4) itself did not produce relaxation. In rats receiving ADDP 14.1mg/kg/day, pulmonary vasodilation induced by calcium ionophore A23187 was augmented and eNOS immunoreactivity was increased. In conclusion, ADDP and HMP are two analogues of BH(4), which can act as oxidatively stable alternatives to BH(4) in causing NO-mediated vasorelaxation. Chronic treatment with ADDP resulted in improvement of NO-mediated pulmonary artery dilation and enhanced expression of eNOS in the pulmonary vascular endothelium. Chemically stable analogues of BH(4) may be able to limit endothelial dysfunction in the pulmonary vasculature.


Asunto(s)
Biopterinas/análogos & derivados , Óxido Nítrico/metabolismo , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/fisiología , Vasodilatación/efectos de los fármacos , Animales , Biopterinas/química , Biopterinas/farmacología , Calcimicina/farmacología , Calcio/metabolismo , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/fisiopatología , Hipoxia/complicaciones , Técnicas In Vitro , Ionóforos/farmacología , Masculino , Óxido Nítrico Sintasa de Tipo III/metabolismo , Pterinas/farmacología , Arteria Pulmonar/metabolismo , Ratas , Ratas Sprague-Dawley
15.
Math Med Biol ; 28(1): 1-29, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20413417

RESUMEN

In this study, we consider a family of mathematical models to describe the elution of drug from polymer-coated stents into the arterial wall. Our models include the polymer layer, the media, the adventitia, a possible topcoat polymer layer and atherosclerotic plaque. We investigate the relative importance of transmural convection, diffusion and drug-dependent parameters in drug delivery and deposition. Furthermore, we investigate how the release rate from the stent can be altered and examine the resulting effect on cellular drug concentrations.


Asunto(s)
Arterias Carótidas/metabolismo , Stents Liberadores de Fármacos , Modelos Cardiovasculares , Placa Aterosclerótica/metabolismo , Arterias Carótidas/efectos de los fármacos , Análisis de Elementos Finitos , Humanos , Placa Aterosclerótica/terapia
16.
Drug Deliv Transl Res ; 1(6): 448-55, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25786365

RESUMEN

Diabetes and its complications have been linked to increased levels of free radicals and systemic pro-inflammatory cytokines and to an altered lipid profile. Coenzyme Q10 and curcumin are potent antioxidants and anti-inflammatory agents but are underutilized clinically because of their poor bioavailability when administered orally. We have recently developed poly(D,L-lactic-co-glycolic acid)-based nanoparticles in which we have encapsulated coenzyme Q10 and curcumin to increase the oral bioavailability and therapeutic efficacy of the antioxidant molecules. These formulations when tested in streptozotocin-induced diabetic rats demonstrated protective effects on inflammatory markers as well as lipid metabolism. Coenzyme Q10 nanoparticulates reduced only C-reactive protein levels, whereas curcumin nanoparticles reduced levels of C-reactive protein, interleukin-6 and tumor necrosis factor-α. Administration of both nanoparticulates resulted in significant reductions of plasma triglycerides and total cholesterol and an increase in high-density lipoprotein cholesterol. Together, these data indicate the promise of coenzyme Q10 and curcumin in diabetes when delivered through nanoparticulate formulations.

17.
Biosens Bioelectron ; 26(2): 661-6, 2010 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-20667708

RESUMEN

Implantable medical devices have become the standard method for treating a variety of cardiovascular diseases (NICE, 2003, 2009), such as coronary artery disease, where coronary artery stents are the device of choice (Fischman et al., 1994; Babapulle et al., 2004). One post-operative problem with these devices is the long-term monitoring of the device-tissue interface, with respect to the complications that often arise from in-stent restenosis. This monitoring, where it is available, is currently performed using imaging techniques such as contrast angiography, IVUS, CT and MRI. In this study we propose an alternative method for the non-invasive monitoring of restenosis in coronary artery stents. This preliminary study uses impedance spectroscopy to measure the electrical impedance of cells and tissues associated with the neointimal growth that characterises in-stent restenosis in coronary artery stents. An in vitro organ culture model, using a stent implanted in a section of pig coronary artery, simulated tissue growth inside a stent. Impedance measurements were made regularly over a 28-day culture period. In a novel step, the stent itself was employed as an electrode. Differences in electrical impedance could be seen between control (stent alone) and artery-embedded stents in culture, which were associated with the presence of biological tissue. This method could potentially be developed to produce a stent that was capable of self-reporting in-stent restenosis. The advantages of such a device would be that monitoring could be non-invasively and easily carried out, allowing more routine follow-ups and the early identification and management of any device complications.


Asunto(s)
Reestenosis Coronaria/fisiopatología , Vasos Coronarios/fisiopatología , Espectroscopía Dieléctrica/métodos , Oclusión de Injerto Vascular/fisiopatología , Neointima/fisiopatología , Stents/efectos adversos , Animales , Neointima/etiología , Porcinos
18.
Eur J Pharmacol ; 641(2-3): 160-7, 2010 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-20450909

RESUMEN

Prostacyclin analogues have the potential to be effective agents in a new generation of drug-eluting stents by virtue of prostanoid IP receptor mediated anti-proliferative effects on smooth muscle cells. However, prostanoid IP receptor mediated vessel relaxation is reduced at elevated analogue concentrations. The mechanisms underlying this loss of activity are unclear, and its influence on the anti-proliferative potential of these compounds remains to be determined. A classical organ bath approach was used to examine the functional response of the rabbit iliac artery to the prostacyclin analogues, AFP-07 and cicaprost. Selective receptor antagonists for prostanoid IP (RO-1138452), EP(1) (SC-51322) and EP(3) (L-798106) receptors were used to characterise the receptors involved. The effects of these agents on proliferation ([(3)H]-thymidine incorporation) of rabbit iliac artery smooth muscle cells stimulated by foetal calf serum were then studied. AFP-07 gave a bell-shaped log concentration-response curve consisting of prostanoid IP receptor mediated relaxation followed by reversal at higher concentrations. SC-51322 and L-798106 potentiated this relaxation, although only L-798106 completely removed the contractile element. The prostanoid EP(3) receptor agonist, sulprostone, produced constriction, which was attenuated by L-798106. RO-1138452 blocked the inhibitory action of AFP-07 and cicaprost on proliferation, implicating an involvement of prostanoid IP receptors. L-798106 had no effect on the anti-proliferative effect of cicaprost, but reduced the effect of AFP-07. Non-selective activation of prostanoid EP(3) receptors (and possibly prostanoid EP(1) receptors) compromises the relaxant activity of prostacyclin analogues, although it does not reduce the anti-proliferative capacity of these compounds in the model studied.


Asunto(s)
Reestenosis Coronaria/fisiopatología , Epoprostenol/análogos & derivados , Arteria Ilíaca/efectos de los fármacos , Prostaglandinas/farmacología , Receptores de Epoprostenol/metabolismo , Animales , Vasos Sanguíneos/efectos de los fármacos , Dinoprostona/agonistas , Dinoprostona/análogos & derivados , Dinoprostona/farmacología , Relación Dosis-Respuesta a Droga , Stents Liberadores de Fármacos/efectos adversos , Epoprostenol/farmacología , Masculino , Contracción Muscular/efectos de los fármacos , Conejos
19.
Ann Vasc Surg ; 24(4): 562-72, 2010 May.
Artículo en Inglés | MEDLINE | ID: mdl-20451798

RESUMEN

A total of 12,000 infrainguinal bypass grafts are performed annually in the United Kingdom, with outcomes suboptimal: 20% of above-knee vein grafts require intervention by 3 years. Transatlantic Inter-Society Consensus (TASC) guidelines exist on pharmacological management of peripheral vascular disease patients, however, little is recommended regarding optimum pharmacological management following revascularization to improve graft patency. The current recommendation is that all patients are on an antiplatelet agent following bypass grafting, the only intervention with significant evidence supporting use. This article will review pharmacological strategies aimed at improving the survival of infrainguinal vein grafts and the current evidence base for their use.


Asunto(s)
Fármacos Cardiovasculares/uso terapéutico , Extremidad Inferior/irrigación sanguínea , Enfermedades Vasculares Periféricas/tratamiento farmacológico , Enfermedades Vasculares Periféricas/cirugía , Procedimientos Quirúrgicos Vasculares , Venas/trasplante , Terapia Combinada , Medicina Basada en la Evidencia , Humanos , Enfermedades Vasculares Periféricas/fisiopatología , Guías de Práctica Clínica como Asunto , Factores de Tiempo , Resultado del Tratamiento , Grado de Desobstrucción Vascular/efectos de los fármacos
20.
Br J Pharmacol ; 159(3): 543-53, 2010 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-20015089

RESUMEN

BACKGROUND AND PURPOSE: Sphingosine-1-phosphate and its receptors may be involved in vascular smooth muscle cell (VSMC) proliferation following vascular injury. Here, we evaluate the effect of d-erythro-N,N-dimethylsphingosine (DMS), a sphingosine kinase (SK) inhibitor, on VSMC proliferation, apoptosis and neointimal formation. EXPERIMENTAL APPROACH: Growth responses in vitro to fetal calf serum (FCS) were measured by [(3)H]-thymidine incorporation and extracellular signal-regulated kinase-1/2 (ERK-1/2) activation in quiescent primary cultures of porcine VSMC in the presence and absence of various concentrations of the SK inhibitor DMS. In vivo treatment with DMS was delivered with a local endoluminal catheter, following balloon injury of coronary arteries. The artery intimal formation was investigated by angiography, myography and histomorphometry. KEY RESULTS: In vitro experiments indicated that DMS induced a dose-dependent reduction in [(3)H]-thymidine incorporation and ERK-1/2 activation via a protein kinase C (PKC) independent mechanism with an IC(50) value of 12 +/- 6 and 15 +/- 10 microM respectively. DMS also reduced Akt signalling. Four weeks following in vivo delivery of DMS, complete functional endothelial regeneration was observed in all treatment groups, with significant reduction of intimal formation (vehicle 23.7 +/- 4.6% vs. DMS infusion 8.92 +/- 2.9%, P < 0.05). CONCLUSIONS AND IMPLICATIONS: Taken together, these results demonstrate that local administration of the SK inhibitor, DMS, reduced neointimal formation, and this effect could involve inhibition of ERK-1/2 and Akt signalling, and modulation of smooth muscle growth.


Asunto(s)
Músculo Liso Vascular/citología , Músculo Liso Vascular/efectos de los fármacos , Esfingosina/farmacología , Túnica Íntima/efectos de los fármacos , Túnica Íntima/patología , Animales , Apoptosis/efectos de los fármacos , Cateterismo , Proliferación Celular/efectos de los fármacos , Hiperplasia/patología , Lisofosfolípidos , Masculino , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/farmacología , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol) , Proteína Quinasa C/metabolismo , Proteína Quinasa C/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Esfingosina/análogos & derivados , Sus scrofa , Túnica Íntima/metabolismo
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