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Int J Mol Sci ; 17(2)2016 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-26805825


Drug-eluting stents (DES) have reduced in-stent-restenosis drastically. Yet, the stent surface material directly interacts with cascades of biological processes leading to an activation of cellular defense mechanisms. To prevent adverse clinical implications, to date almost every patient with a coronary artery disease is treated with statins. Besides their clinical benefit, statins exert a number of pleiotropic effects on endothelial cells (ECs). Since maintenance of EC function and reduction of uncontrolled smooth muscle cell (SMC) proliferation represents a challenge for new generation DES, we investigated the effect of atorvastatin (ATOR) on human coronary artery cells grown on biodegradable polymers. Our results show a cell type-dependent effect of ATOR on ECs and SMCs. We observed polymer-dependent changes in IC50 values and an altered ATOR-uptake leading to an attenuation of statin-mediated effects on SMC growth. We conclude that the selected biodegradable polymers negatively influence the anti-proliferative effect of ATOR on SMCs. Hence, the process of developing new polymers for DES coating should involve the characterization of material-related changes in mechanisms of drug actions.

Atorvastatina/farmacologia , Plásticos Biodegradáveis/farmacologia , Vasos Coronários/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Polímeros/farmacologia , Técnicas de Cultura de Células , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doença da Artéria Coronariana/tratamento farmacológico , Vasos Coronários/efeitos dos fármacos , Stents Farmacológicos , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Humanos , Miócitos de Músculo Liso/citologia , Especificidade de Órgãos , Propriedades de Superfície
Vascul Pharmacol ; 72: 25-34, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26091578


Clinical success of coronary drug-eluting stents (DES) is hampered by simultaneous reduction of smooth muscle cell (HCASMC) and endothelial cell proliferation due to unspecific cytotoxicity of currently used compounds. Previous in vitro data showing SMC-specific inhibition of proliferation suggested that statins may be suitable candidates for DES. It was aim of this study to further investigate statins as DES drug candidates to identify mechanisms contributing to their cell-selectivity. In vitro proliferation assays comparing the influence of various statins on HCASMC and endothelial cells confirmed that atorvastatin exhibits HCASMC-specificity. Due to similar expression levels of the drug target HMG-CoA reductase in both cell types, cellular accumulation of atorvastatin was assessed, revealing enhanced uptake in HCASMC most likely driven by significant expression of OATP2B1, a known uptake transporter for atorvastatin. In accordance with the finding that endogenous OATP2B1 influenced cellular accumulation in HCASMC we used this transporter as a tool to identify teniposide as new DES candidate drug with HCASMC-specific effects. We describe OATP2B1 as a determinant of pharmacokinetics in the coronary artery. Indeed, endogenously expressed OATP2B1 significantly influences the uptake of substrate drugs, thereby governing cell specificity. Screening of candidate drugs for interaction with OATP2B1 may be used to promote SMC-specificity.

Atorvastatina/farmacologia , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Transportadores de Ânions Orgânicos/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo
Mol Pharm ; 11(3): 665-72, 2014 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-24495124


Enhanced proliferation of human coronary artery smooth muscle cells (HCASMCs) and thereby formation of neointima is one of the factors contributing to failure of coronary stents. Even if the use of drug eluting stents (DES) and thereby the local delivery of cytotoxic compounds has significantly improved the clinical outcome, unselective cytotoxic effects are assumed to hamper clinical success. Novel pharmacological approaches are required to enhance cellular selectivity of locally delivered drugs. Cell specific overexpression of a drug transporter could be used to enhance cellular accumulation and therefore cell specificity. In the herein reported study we tested the possibility of cell specific transporter expression to enhance drug effects in HCASMCs. We generated adenoviral constructs to overexpress the organic cation transporter 1 (OCT1) under control of the promoter of SM22α, which had been previously reported as muscle cell specific gene. First the activity of the SM22α-promoter was assessed in various cell types supporting the notion of muscle cell specificity. Subsequently, the activity of the transporter was compared in infected HCAECs and HCASMCs revealing enhanced accumulation of substrate drugs in HCASMCs in presence of the SM22α-promoter. Testing the hypothesis that this kind of targeting might serve as a mechanism for cell-specific drug effects, we investigated the impact on paclitaxel treatment in HCASMC and HCAECs, showing significantly increased antiproliferative activity of this substrate drug on muscle cells. Taken together, our findings suggest that cell-specific expression of transport proteins serves as mechanism governing the uptake of cytotoxic compounds for a selective impact on targeted cells.

Vasos Coronários/metabolismo , Endotélio Vascular/metabolismo , Células Madin Darby de Rim Canino/metabolismo , Proteínas dos Microfilamentos/genética , Proteínas Musculares/genética , Músculo Liso Vascular/metabolismo , Miócitos Cardíacos/metabolismo , Transportador 1 de Cátions Orgânicos/metabolismo , Adenoviridae/genética , Animais , Antineoplásicos Fitogênicos/farmacologia , Western Blotting , Fármacos Cardiovasculares/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Vasos Coronários/citologia , Vasos Coronários/efeitos dos fármacos , Cães , Sistemas de Liberação de Medicamentos , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Células Madin Darby de Rim Canino/citologia , Células Madin Darby de Rim Canino/efeitos dos fármacos , Camundongos , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Transportador 1 de Cátions Orgânicos/genética , Paclitaxel/farmacologia , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
J Mater Sci Mater Med ; 24(11): 2589-600, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23846839


Within the context of novel stent designs we developed a dual drug-eluting stent (DDES) with an abluminally focussed release of the potent anti-proliferative drug sirolimus and a luminally focussed release of atorvastatin with stabilizing effect on atherosclerotic deposits and stimulating impact on endothelial function, both from biodegradable poly(L-lactide)-based stent coatings. With this concept we aim at simultaneous inhibition of in-stent restenosis as a result of disproportionally increased smooth muscle cell proliferation and migration as well as thrombosis due to failed or incomplete endothelialisation. The especially adapted spray-coating processes allowed the formation of smooth form-fit polymer coatings at the abluminal and luminal side with 70% respectively 90% of the drug/polymer solution being deposited at the intended stent surface. The impacts of tempering, sterilization, and layer composition on drug release are thoroughly discussed making use of a semi-empirical model. While tempering at 80 °C seems to be necessary for the achievement of adequate and sustained drug release, the coating sequence for DDES should be rather abluminal-luminal than luminal-abluminal, as reduction of the amount of sirolimus eluted luminally could then potentially minimize the provocation of endothelial dysfunction. In vitro proliferation and viability assays with smooth muscle and endothelial cells underline the high potential of the developed DDES.

Stents Farmacológicos , Ácidos Heptanoicos/administração & dosagem , Pirróis/administração & dosagem , Sirolimo/administração & dosagem , Atorvastatina , Varredura Diferencial de Calorimetria , Proliferação de Células , Células Cultivadas , Ácidos Heptanoicos/farmacologia , Humanos , Técnicas In Vitro , Microscopia Eletrônica de Varredura , Peso Molecular , Pirróis/farmacologia , Sirolimo/farmacologia
J Biomed Mater Res B Appl Biomater ; 100(1): 41-50, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22114061


Magnesium-based bioabsorbable cardiovascular stents have been developed to overcome limitations of permanent metallic stents, such as late stent thrombosis. During stent degradation, endothelial and smooth muscle cells will be exposed to locally high magnesium concentrations with yet unknown physiological consequences. Here, we investigated the effects of elevated magnesium concentrations on human coronary artery endothelial and smooth muscle cell (HCAEC, HCASMC) growth and gene expression. In the course of 24 h after incubation with magnesium chloride solutions (1 or 10 mM) intracellular magnesium level in HCASMC raised from 0.55 ± 0.25 mM (1 mM) to 1.38 ± 0.95 mM (10 mM), while no increase was detected in HCAEC. Accordingly, a DNA microarray-based study identified 69 magnesium regulated transcripts in HCAEC, but 2172 magnesium regulated transcripts in HCASMC. Notably, a significant regulation of various growth factors and extracellular matrix components was observed. In contrast, viability and proliferation of HCAEC were increased at concentrations of up to 25 mM magnesium chloride, while in HCASMC viability and proliferation appeared to be unaffected. Taken together, our data indicate that magnesium halts smooth muscle cell proliferation and stimulates endothelial cell proliferation, which might translate into a beneficial effect in the setting of stent associated vascular injury.

Implantes Absorvíveis , Proliferação de Células , Vasos Coronários/metabolismo , Células Endoteliais/metabolismo , Magnésio , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Stents , Sobrevivência Celular , Células Cultivadas , Vasos Coronários/citologia , Vasos Coronários/lesões , Células Endoteliais/citologia , Regulação da Expressão Gênica , Humanos , Teste de Materiais/métodos , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/citologia