Atorvastatin Inhibits Src/ROS-mediated Redox Sensitive And Pro-Inflammatory Actions of Aldosterone in Vascular Smooth Muscle Cells: Focus on Statins Pleiotropic Effects

Bruder-Nascimento, T., Callera, G. E., Montezano, A. C., He, Y., Antunes, T., de Cassia Tostes, R., Touyz, R. M. and , (2013) Atorvastatin Inhibits Src/ROS-mediated Redox Sensitive And Pro-Inflammatory Actions of Aldosterone in Vascular Smooth Muscle Cells: Focus on Statins Pleiotropic Effects. Hypertension, 62(3 Sup), A488.

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Publisher's URL: http://hyper.ahajournals.org/cgi/content/meeting_abstract/62/3_MeetingAbstracts/A488

Abstract

Statins, described as cholesterol-lowering drugs, are now recognized to induce effects throught pleiotropic actions, including oxidative stress reduction and protein geranylgeranylation inhibition. Mechanisms whereby aldosterone associates with c-Src and related redox signaling molecules involve lipid rafts. This study aims to identify whether c-Src/NADPH oxidases (Nox) pathway is a statin-sensitive target independent of membrane cholesterol depletion mechanisms. In order to discriminate statin pleiotropic effects from its classic cholesterol synthesis inhibition, VSMCs from WKY were treated with 1 uM atorvastatin for 60 min or 72h prior 100 nM aldosterone stimulations respectively. Aldosterone-induced c-Src phosphorylation (% vehicle, 267 ± 35) was inhibited by long (150 ± 23 %) and short (114 ± 33 %) term atorvastatin treatment. To restore cholesterol synthesis, cells were incubated with its intermediate, mevalonate (100 μM). Mevalonate reload restored c-Src phosphorylation (287 ± 27 %) induced by aldosterone in atorvastatin long term-treated VSMCs. Geranylgeranyl-pyrophosphate (GGPP) was used to prevent protein geranylgeranylation inhibition. GGPP reposition recovered the effects of aldosterone on c-Src phosphorylation in both short (268 ± 22 %) and long (203 ± 35 %) term VSMCs treated with atorvastatin. Aldosterone-induced increase of Nox1, 2 and 4 expression and the associated ROS-generation (215 ± 38 %) were inhibited by long and short term atorvastatin incubation. Aldosterone-induced RAC1/2 and p47phox translocation (cytosol to membrane) was prevented by atorvastatin treatments. Aldosterone stimulation increased Nox1 and p47phox content in cholesterol-enriched fractions, an effect inhibited by atorvastatin short term treatment. Atorvastatin also prevented the increase of redox-signaling phosphorylation (ERK1/2, p38 and JNK) and pro-inflammatory markers (VCAM-1 expression, NFkB p65 phosphorylation) by aldosterone. We demonstrate that atorvastatin influences c-Src/Nox-mediated effects of aldosterone involving lipid rafts through classic and pleiotropic actions independent of cholesterol depletion. This study identifies a novel mechanism for statins in aldosterone-associated vascular injury.

Item Type:Articles
Additional Information:American-Heart-Association High Blood Pressure Research Scientific Sessions, New Orleans, LA, USA, 11-14 Sept 2013.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Montezano, Dr Augusto and Touyz, Professor Rhian
Authors: Bruder-Nascimento, T., Callera, G. E., Montezano, A. C., He, Y., Antunes, T., de Cassia Tostes, R., Touyz, R. M., and ,
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Hypertension
Publisher:American Heart Association
ISSN:0194-911X
ISSN (Online):1524-4563

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
607382Vascular Noxs as therapeutic targets and biomarkers in hypertensionRhian TouyzBritish Heart Foundation (BHF)RG/13/7/30099RI CARDIOVASCULAR & MEDICAL SCIENCES