The pleiotropic effects of simvastatin on retinal microvascular endothelium has important implications for ischaemic retinopathies.

<h4>Background</h4>Current guidelines encourage the use of statins to reduce the risk of cardiovascular disease in diabetic patients; however the impact of these drugs on diabetic retinopathy is not well defined. Moreover, pleiotropic effects of statins on the highly specialised retinal...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Reinhold J Medina, Christina L O'Neill, Adrian B Devine, Tom A Gardiner, Alan W Stitt
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2008
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a2ff1159eaff41ea86bf0e760e742072
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:a2ff1159eaff41ea86bf0e760e742072
record_format	dspace
spelling	oai:doaj.org-article:a2ff1159eaff41ea86bf0e760e7420722021-11-25T06:11:43ZThe pleiotropic effects of simvastatin on retinal microvascular endothelium has important implications for ischaemic retinopathies.1932-620310.1371/journal.pone.0002584https://doaj.org/article/a2ff1159eaff41ea86bf0e760e7420722008-07-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18612412/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Current guidelines encourage the use of statins to reduce the risk of cardiovascular disease in diabetic patients; however the impact of these drugs on diabetic retinopathy is not well defined. Moreover, pleiotropic effects of statins on the highly specialised retinal microvascular endothelium remain largely unknown. The objective of this study was to investigate the effects of clinically relevant concentrations of simvastatin on retinal endothelium in vitro and in vivo.<h4>Methods and findings</h4>Retinal microvascular endothelial cells (RMECs) were treated with 0.01-10 microM simvastatin and a biphasic dose-related response was observed. Low concentrations enhanced microvascular repair with 0.1 microM simvastatin significantly increasing proliferation (p<0.05), and 0.01 microM simvastatin significantly promoting migration (p<0.05), sprouting (p<0.001), and tubulogenesis (p<0.001). High concentration of simvastatin (10 microM) had the opposite effect, significantly inhibiting proliferation (p<0.01), migration (p<0.01), sprouting (p<0.001), and tubulogenesis (p<0.05). Furthermore, simvastatin concentrations higher than 1 microM induced cell death. The mouse model of oxygen-induced retinopathy was used to investigate the possible effects of simvastatin treatment on ischaemic retinopathy. Low dose simvastatin (0.2 mg/Kg) promoted retinal microvascular repair in response to ischaemia by promoting intra-retinal re-vascularisation (p<0.01). By contrast, high dose simvastatin(20 mg/Kg) significantly prevented re-vascularisation (p<0.01) and concomitantly increased pathological neovascularisation (p<0.01). We also demonstrated that the pro-vascular repair mechanism of simvastatin involves VEGF stimulation, Akt phosphorylation, and nitric oxide production; and the anti-vascular repair mechanism is driven by marked intracellular cholesterol depletion and related disorganisation of key intracellular structures.<h4>Conclusions</h4>A beneficial effect of low-dose simvastatin on ischaemic retinopathy is linked to angiogenic repair reducing ischaemia, thereby preventing pathological neovascularisation. High-dose simvastatin may be harmful by inhibiting reparative processes and inducing premature death of retinal microvascular endothelium which increases ischaemia-induced neovascular pathology. Statin dosage should be judiciously monitored in patients who are diabetic or are at risk of developing other forms of proliferative retinopathy.Reinhold J MedinaChristina L O'NeillAdrian B DevineTom A GardinerAlan W StittPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 3, Iss 7, p e2584 (2008)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Reinhold J Medina Christina L O'Neill Adrian B Devine Tom A Gardiner Alan W Stitt The pleiotropic effects of simvastatin on retinal microvascular endothelium has important implications for ischaemic retinopathies.
description	<h4>Background</h4>Current guidelines encourage the use of statins to reduce the risk of cardiovascular disease in diabetic patients; however the impact of these drugs on diabetic retinopathy is not well defined. Moreover, pleiotropic effects of statins on the highly specialised retinal microvascular endothelium remain largely unknown. The objective of this study was to investigate the effects of clinically relevant concentrations of simvastatin on retinal endothelium in vitro and in vivo.<h4>Methods and findings</h4>Retinal microvascular endothelial cells (RMECs) were treated with 0.01-10 microM simvastatin and a biphasic dose-related response was observed. Low concentrations enhanced microvascular repair with 0.1 microM simvastatin significantly increasing proliferation (p<0.05), and 0.01 microM simvastatin significantly promoting migration (p<0.05), sprouting (p<0.001), and tubulogenesis (p<0.001). High concentration of simvastatin (10 microM) had the opposite effect, significantly inhibiting proliferation (p<0.01), migration (p<0.01), sprouting (p<0.001), and tubulogenesis (p<0.05). Furthermore, simvastatin concentrations higher than 1 microM induced cell death. The mouse model of oxygen-induced retinopathy was used to investigate the possible effects of simvastatin treatment on ischaemic retinopathy. Low dose simvastatin (0.2 mg/Kg) promoted retinal microvascular repair in response to ischaemia by promoting intra-retinal re-vascularisation (p<0.01). By contrast, high dose simvastatin(20 mg/Kg) significantly prevented re-vascularisation (p<0.01) and concomitantly increased pathological neovascularisation (p<0.01). We also demonstrated that the pro-vascular repair mechanism of simvastatin involves VEGF stimulation, Akt phosphorylation, and nitric oxide production; and the anti-vascular repair mechanism is driven by marked intracellular cholesterol depletion and related disorganisation of key intracellular structures.<h4>Conclusions</h4>A beneficial effect of low-dose simvastatin on ischaemic retinopathy is linked to angiogenic repair reducing ischaemia, thereby preventing pathological neovascularisation. High-dose simvastatin may be harmful by inhibiting reparative processes and inducing premature death of retinal microvascular endothelium which increases ischaemia-induced neovascular pathology. Statin dosage should be judiciously monitored in patients who are diabetic or are at risk of developing other forms of proliferative retinopathy.
format	article
author	Reinhold J Medina Christina L O'Neill Adrian B Devine Tom A Gardiner Alan W Stitt
author_facet	Reinhold J Medina Christina L O'Neill Adrian B Devine Tom A Gardiner Alan W Stitt
author_sort	Reinhold J Medina
title	The pleiotropic effects of simvastatin on retinal microvascular endothelium has important implications for ischaemic retinopathies.
title_short	The pleiotropic effects of simvastatin on retinal microvascular endothelium has important implications for ischaemic retinopathies.
title_full	The pleiotropic effects of simvastatin on retinal microvascular endothelium has important implications for ischaemic retinopathies.
title_fullStr	The pleiotropic effects of simvastatin on retinal microvascular endothelium has important implications for ischaemic retinopathies.
title_full_unstemmed	The pleiotropic effects of simvastatin on retinal microvascular endothelium has important implications for ischaemic retinopathies.
title_sort	pleiotropic effects of simvastatin on retinal microvascular endothelium has important implications for ischaemic retinopathies.
publisher	Public Library of Science (PLoS)
publishDate	2008
url	https://doaj.org/article/a2ff1159eaff41ea86bf0e760e742072
work_keys_str_mv	AT reinholdjmedina thepleiotropiceffectsofsimvastatinonretinalmicrovascularendotheliumhasimportantimplicationsforischaemicretinopathies AT christinaloneill thepleiotropiceffectsofsimvastatinonretinalmicrovascularendotheliumhasimportantimplicationsforischaemicretinopathies AT adrianbdevine thepleiotropiceffectsofsimvastatinonretinalmicrovascularendotheliumhasimportantimplicationsforischaemicretinopathies AT tomagardiner thepleiotropiceffectsofsimvastatinonretinalmicrovascularendotheliumhasimportantimplicationsforischaemicretinopathies AT alanwstitt thepleiotropiceffectsofsimvastatinonretinalmicrovascularendotheliumhasimportantimplicationsforischaemicretinopathies AT reinholdjmedina pleiotropiceffectsofsimvastatinonretinalmicrovascularendotheliumhasimportantimplicationsforischaemicretinopathies AT christinaloneill pleiotropiceffectsofsimvastatinonretinalmicrovascularendotheliumhasimportantimplicationsforischaemicretinopathies AT adrianbdevine pleiotropiceffectsofsimvastatinonretinalmicrovascularendotheliumhasimportantimplicationsforischaemicretinopathies AT tomagardiner pleiotropiceffectsofsimvastatinonretinalmicrovascularendotheliumhasimportantimplicationsforischaemicretinopathies AT alanwstitt pleiotropiceffectsofsimvastatinonretinalmicrovascularendotheliumhasimportantimplicationsforischaemicretinopathies
_version_	1718414060423217152

The pleiotropic effects of simvastatin on retinal microvascular endothelium has important implications for ischaemic retinopathies.

Ejemplares similares