Low-dose treatment with atorvastatin leads to anti-oxidative and anti-inflammatory effects in diabetes mellitus

We investigated whether atorvastatin, given in a dose to low to influence the lipid profile, has any effect on oxidative stress, inflammation and endothelial function under streptozotocin-induced diabetic conditions. Diabetes mellitus was induced in male Sprague Dawley rats by a single injection of streptozotocin. Rats were treated chronically with atorvastatin (50 mg/kg/day; p.o.) or vehicle until day 48 and compared with controls. NAD(P)H activity, protein expression nuclear factor-kappa Bp65 (NF-kappa Bp65) and phosphorylation of the extracellular signal-regulated kinase (ERK1/2) were assessed in the quadriceps muscle. Protein and mRNA levels of intracellular and vascular adhesion molecules (ICAM-1, VCAM-1) and cytokines were measured by Taqman or immunohistochemistry staining, respectively. Endothelial function was investigated in vivo using the autoperfused hind limb model. Diabetic groups displayed similar severe hyperglycemia. Untreated diabetic rats showed enhanced NAD(P)H activity, activation of the ERK 1/2/NF-kappa Bp65-pathway, enhanced expression of cytokines and cellular adhesion molecules and impaired vascular function. Low-dose therapy by atorvastatin did not alter the lipid profile but led to a reduction of NAD(P)H activity (-28%, P < 0.05) associated with reduced protein expression of NF-kappa Bp65 (-53%, P < 0.05) and phosphorylation of its regulator mitogen-activated protein kinase (MAPK) ERK1/2 in diabetic rats. Also inflammatory markers were reduced after atorvastatin treatment indexed by reduced mRNA expression of VCAM-1 (-24%), tumor necrosis factor a (-59%)and interleukin 1 (-50%) and reduced ICAM-1 (-81%) and VCAM-1 (-74%) positive staining. These beneficial effects were associated with improved endothelium-dependent vasodilatation (maximal vasodilatation: +101%; P < 0.05). Lipid-independent antioxidative and anti-inflammatory effects of low-dose atorvastatin involving the ERK1/2/NF-kappa B-pathway are sufficient to improve endothelial function under experimental diabetic conditions. (c) 2007 Elsevier B.V. All rights reserved.