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-kappaBp65 (NF-kappaBp65) 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 ERK1/2/NF-kappaBp65-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-kappaBp65 (-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 alpha (-59%) and interleukin 1beta (-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 anti-oxidative and anti-inflammatory effects of low-dose atorvastatin involving the ERK1/2/NF-kappaB-pathway are sufficient to improve endothelial function under experimental diabetic conditions.
Riad
Alexander
A
Department of Cardiology and Pneumology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12206 Berlin, Germany.
Du
Jing
J
Stiehl
Sebastian
S
Westermann
Dirk
D
Mohr
Zarah
Z
Sobirey
Meike
M
Doehner
Wolfram
W
Adams
Volker
V
Pauschinger
Matthias
M
Schultheiss
Heinz Peter
HP
Tschöpe
Carsten
C
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology*; D000069059:Atorvastatin; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy*; D004730:Endothelium, Vascular / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism; D019255:NADPH Oxidases / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D051996:Transcription Factor RelA / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D000924:Anticholesteremic Agents; D000975:Antioxidants; D006538:Heptanoic Acids; D018836:Inflammation Mediators; D011758:Pyrroles; D012333:RNA, Messenger; D051996:Transcription Factor RelA; D013311:Streptozocin; D000069059:Atorvastatin; D019255:NADPH Oxidases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3