Abstract 1691: Atorvastatin Treatment reduces Vascular Oxidative Stress and improves Endothelial Dysfunction in Streptozotocin-induced Diabetes Mellitus by increasing the Expression of GTP-Cyclohydrolase I
Background: Studies in diabetic animals and patients identified an uncoupled nitric oxide synthase as an important superoxide source. Endothelial dysfunction and impairement of endothelial progenitor cell (EPC) mobilization and function has been shown to be secondary to increased vascular reactive oxygen species (ROS) production in diabetes mellitus (DM). In the present study we sought to determine the effects of atorvastatin treatment (ator) on eNOS coupling, oxidative stress and endothelial dysfunction in a rat model of streptozotocin (STZ)-induced DM.
Methods: Male Wistar rats were devided into 4 groups (ctr, ator, STZ, STZ/ator). Diabetes was induced by a single i.v. injection of STZ (60 mg/kg). Ator feeding (20 mg/kg/d) started one day after STZ injection. After 7 weeks, we determined vascular function by isometric tension studies, expression of GTP-cyclohydrolase (GCH-1), eNOS, P-VASP and NADPH-oxidase subunits by Western blot analysis, ROS formation by L-012 enhanced chemiluminescence and tetrahydrobiopterin (BH4) levels by mass spectrometry.
Results: Acetylcholin (ACh) and nitroglycerin (NTG)-dependent relaxation was markedly impaired and ROS formation in intact aortic rings and in NADPH-stimulated heart membrane fractions (hMF) was increased (1,55- and 2-fold vs ctr, respectively) in STZ (p<0,05). In STZ, EPC levels were decreased (44% of ctr); in hMF, expression of the NADPH-oxidase subunits nox1, nox2 and p67phox increased 4,5-, 2,5- and 2,5-fold, respectively (p<0,05 vs ctr). The decreased expression of aortic GCH-1 in STZ (36% of ctr) was substantially increased by ator treatment (86% of ctr). Likewise, reduced BH4 levels normalized in STZ/ator (p<0,05 vs ctr). Ator completely normalized impaired ACh- and NTG-dependent relaxation, normalized expression of the NADPH oxidase subunits and accordingly decreased ROS formation significantly. Ator influenced glucose homeostasis positively, while plasma lipid levels were not modified at all.
Conclusion: Ator improves endothelial dysfunction and reduces oxidative stress in an animal model of STZ-diabetes by normalizing the expression of the vascular NADPH oxidase and by recoupling eNOS due to regeneration of the pacemaker enzyme for BH4-synthesis, GCH-1.