A novel mechanism of action for statins against diabetes-induced oxidative stress

C. Vecchione, M. T. Gentile, A. Aretini, G. Marino, R. Poulet, A. Maffei, F. Passarelli, A. Landolfi, A. Vasta, G. Lembo

Research output: Contribution to journalArticle

Abstract

Aims/hypothesis: Atorvastatin exerts beneficial vascular effects in diabetes, but the underlying mechanisms are yet to be elucidated. The aim of the present study was to determine whether Rac-1 is involved in the effect of atorvastatin on oxidative stress and vascular dysfunction. Materials and methods: Using human aortic endothelial cells (HAECs) we evaluated the effect of high glucose levels on peroxide production by dihydrodichlorofluorescein and on Rac-1 activity using immunocytochemistry to detect Rac-1 translocation to the membrane. We evaluated vascular function, peroxide production by dihydroethidium and NADPH oxidase activity in vessels from atorvastatin-treated mice. Rac-1 activity was also assessed, both by immunoprecipitation of the Rac-p21-activated kinase complex and by analysis of Rac-1 translocation to the membrane. These experiments were also conducted in vessels infected with an adenoviral vector carrying a constitutively active mutant of Rac-1. Results: In HAECs exposed to high glucose levels, atorvastatin prevented oxidative stress, and this protection was associated with impaired Rac-1 activation. This effect was also observed in a murine model of diabetes mellitus. More importantly, the addition of geranylgeranyl pyrophosphate (GGPP) blocked the effects of atorvastatin in both glucose-exposed HAECs and diabetic vessels. Atorvastatin failed to afford protection against vascular abnormalities in the presence of a constitutively active mutant of Rac-1. Conclusions/interpretation: The results of this study demonstrate that the vascular antioxidant effect of atorvastatin in diabetes is mediated through inhibition of Rac-1 via a reduction in GGPP. Thus, selective Rac-1 inhibition should be considered in the design of novel pharmacological strategies to reduce the impact of diabetes mellitus on vascular function.

Original languageEnglish
Pages (from-to)874-880
Number of pages7
JournalDiabetologia
Volume50
Issue number4
DOIs
Publication statusPublished - Apr 2007

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Hydroxymethylglutaryl-CoA Reductase Inhibitors
Oxidative Stress
Blood Vessels
Endothelial Cells
Peroxides
Glucose
Diabetes Mellitus
p21-Activated Kinases
Membranes
NADPH Oxidase
Atorvastatin Calcium
Immunoprecipitation
Antioxidants
Immunohistochemistry
Pharmacology

Keywords

  • Atorvastatin
  • Diabetes
  • Oxidative stress
  • Rac-1

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

A novel mechanism of action for statins against diabetes-induced oxidative stress. / Vecchione, C.; Gentile, M. T.; Aretini, A.; Marino, G.; Poulet, R.; Maffei, A.; Passarelli, F.; Landolfi, A.; Vasta, A.; Lembo, G.

In: Diabetologia, Vol. 50, No. 4, 04.2007, p. 874-880.

Research output: Contribution to journalArticle

Vecchione, C. ; Gentile, M. T. ; Aretini, A. ; Marino, G. ; Poulet, R. ; Maffei, A. ; Passarelli, F. ; Landolfi, A. ; Vasta, A. ; Lembo, G. / A novel mechanism of action for statins against diabetes-induced oxidative stress. In: Diabetologia. 2007 ; Vol. 50, No. 4. pp. 874-880.
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AU - Gentile, M. T.

AU - Aretini, A.

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AU - Poulet, R.

AU - Maffei, A.

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AU - Vasta, A.

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