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


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
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.
Vecchione
C
C
Department of Angio-cardio-neurology, IRCCS Neuromed, Località Camerelle, 86077, Pozzilli (IS), Italy.
Gentile
M T
MT
Aretini
A
A
Marino
G
G
Poulet
R
R
Maffei
A
A
Passarelli
F
F
Landolfi
A
A
Vasta
A
A
Lembo
G
G
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001011:Aorta / Q000166:cytology; D000069059:Atorvastatin; D048909:Diabetes Complications / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000188:drug therapy*; D042783:Endothelial Cells / Q000166:cytology; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D020744:rac GTP-Binding Proteins / Q000378:metabolism
D000975:Antioxidants; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D011758:Pyrroles; D000069059:Atorvastatin; D020744:rac GTP-Binding Proteins; C002963:geranylgeranyl pyrophosphate