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Statin-induced reduction of inflammation improves endothelial function in an experimental model of diabetic angiopathy
Durch Statin induzierte Reduktion von Inflammation verbessert die endotheliale Funktion in einem experimentellen Modell der diabetischen Angiopathie
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Veröffentlicht: | 10. August 2005 |
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Background: Endothelial dysfunction is the central pathophysiological denominator for all cardiovascular complications of diabetes. The present study was designed to investigate the effects of atorvastatin (Ator)-treatment at a dose too low to decrease LDL cholesterol, on nitric oxide (NO)- and endothelium-dependent vasodilatation in streptozotocin (STZ)-induced diabetic rats.
Methods: Diabetes was induced by a single injection of STZ (70 mg/kg, i.p.) in 8 weeks old Sprague Dawley (SD) rats. Diabetic rats were treated with Ator (50 mg/kg/day; per gavage) or with vehicle for 7 weeks. Age-matched non-diabetic SD rats were used as controls. The vasoactive responses to basal and stimulated endothelial NO were studied in anaesthetized intubated and ventilated rats by using the isolated autoperfused hindlimb model. NO- and endothelial-dependent dilatation was analyzed by induction of shear stress. Vascular cell adhesion molecule (VCAM)-1, interleukin (IL)-1b and tumor necrosis factor (TNF)-a mRNA expression in the hindlimb was quantified by real time RT-PCR. Nuclear factor (NF)-kB p65, phospho (p) and total (tot.) extracellular signal-regulated (ERK) 1/2-kinase protein levels in the hindlimb were quantified by Western-Blot.
Results: Diabetes was associated with increased VCAM-1, IL-1b, TNF-a and NF-kB p65 expression and induced phosphorylation of the ERK1/2 kinases. These findings correlated with impaired endothelial function. Ator-treatment downregulated diabetes-induced VCAM-1, IL-1b, TNF-a and NF-kB expression 1.3-, 2.0-, 2.4- and 1.5-fold respectively (p<0.05) and reduced the p-ERK1/tot.ERK1 and the p-ERK2/tot.ERK2 ratio 2.9- and 1.9-fold, respectively (p<0.05). These findings correlated with significantly improved NO- and endothelial-dependent vasodilatation. Dyslipidemia was not affected by Ator-treatment.
Conclusion: Low dose Ator reduces diabetes-associated inflammation, which involves the ERK kinase- and NF-kB-pathway, resulting in improved angiopathy.