RESUMO
Endothelial cells and smooth muscle cells are the major cells that constitute blood vessels, and endothelial cells line the lumen of blood vessels. These 2 types of cells also play an integral role in the regional specialization of vascular structure. On the basis of these observations, we designed our study to investigate the effect of various statins on CYP expression in endothelial cells. 3-hydroxymethyl coenzyme A reductase inhibitors play an important role in vascular function. The majority of the statins available on the market show extensive metabolism by cytochrome P450 (CYP) enzymes. Both cell types are involved in the bioconversion of arachidonic acid into vasoactive compounds. The aim of this study was to demonstrate the effect of statins on cytochrome P450 expression in endothelial cells. Our results show that endothelial cells expressed both CYPs involved in epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoic acids (HETEs) production and the nuclear receptor implicated in cytochrome P450 regulation. Treatment of endothelial cells with lovastatin increased CYP2C9 expression. After 96 hours of treatment, fluvastatin and lovastatin clearly increased CYP2C9 protein level. CAR but not PXR was expressed in endothelial cells, indicating that the upregulating effect of statins on CYP2C9 in endothelial cells could be mediated through CAR only due to the lack of expression of PXR in these cells.
Assuntos
Sistema Enzimático do Citocromo P-450/biossíntese , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/enzimologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Análise de Variância , Hidrocarboneto de Aril Hidroxilases/efeitos dos fármacos , Hidrocarboneto de Aril Hidroxilases/metabolismo , Atorvastatina , Western Blotting , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Receptor Constitutivo de Androstano , Citocromo P-450 CYP2C9 , Endotélio Vascular/citologia , Ácidos Graxos Monoinsaturados/farmacologia , Fluvastatina , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Ácidos Heptanoicos/farmacologia , Humanos , Indóis/farmacologia , Lovastatina/farmacologia , Pravastatina/farmacologia , Receptor de Pregnano X , Pirróis/farmacologia , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Receptores Citoplasmáticos e Nucleares/biossíntese , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Receptores de Glucocorticoides/biossíntese , Receptores de Glucocorticoides/efeitos dos fármacos , Receptores de Esteroides/biossíntese , Receptores de Esteroides/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Veia Safena/citologia , Fatores de Transcrição/biossíntese , Fatores de Transcrição/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
The expression of cytochrome P450 (CYP) enzymes and cyclo-oxygenases (COX) was investigated in human saphenous veins by reverse transcription-polymerase chain reaction analysis. Non-varicose veins were obtained from patients undergoing aortocoronary bypass grafting, whereas varicose veins were obtained from patients undergoing stripping removal of varicose saphenous veins. In non-varicose veins, CYP1B1, CYP2C, CYP2E1 and CYP4A11 were detected, whereas CYP2J2, CYP3A5, COX-1 and COX-2 were detected almost exclusively in varicose veins. CYP4F2 was not detectable. Except for CYP4A11, the levels of individual CYP mRNA were higher in varicose veins than in control veins. Smooth muscle cell volume, determined by a colour image-analysis system, was increased approximately 1.5-fold in varicose veins. Because CYPs and COXs produce various vasoactive compounds, increased expression of these enzymes could be involved in the impairment of vascular tone and may contribute to varicose pathology. Then, CYP or COX modulators may be potentially active in the treatment of chronic venous insufficiency.
