Abstract 1434: Rac-1 Is Activated In Vessels From Diabetic Patients And Represents A Target Of Statin Treatment
Oxidative stress plays a crucial role in the vascular dysfunction present in diabetes mellitus. Statin treatment blunts oxidative stress and improve vascular function in diabetic mice through the inhibition of Rac-1, a small G protein involved in NADPH oxidase activation. So far there are no data in diabetic patients on Rac-1 activation and its modulation by statin treatment. To clarify this issue we selected two group of diabetic patients: treated with statins (n=9) and without treatment with statin (n=8). Tyroid arteries removed from patients subjected to carotid surgery were analyzed with acetylcholine and bradykinin to test endothelial relaxation and with nitroglycerin for smooth muscle function. Our results demonstrate that vessels of diabetic patients treated with statin show a better endothelial relaxation as compared to that observed in untreated diabetic patients (acetylcholine, % max vasorelaxation: 87±3 vs 44±2, p<0.01), (bradykinin, % max vasorelaxation: 81±4 vs 51±3, p<0.02) In contrast, smooth muscle relaxation is comparable between the two groups. In addition, vessels from diabetic patients treated with statins show a blunted oxidative stress, evaluated by dihydroetidium, as compared to vessels of untreated diabetic patients. Moreover, NADPH oxidase activity, evaluated by lucigenin assay, is significantly reduced in vessels from treated diabetic patients as compared to those untreated. Finally, the analysis of Rac-1 activation through the evaluation of Rac-1/PAK complex by western blotting show that Rac-1 is markedly activated in vessels from untreated diabetic patients as compared to that observed in vessels from diabetic patients treated with statin. The results of our study demonstrate, for the first time in human, that Rac-1 is activated in the vessels of diabetic patients. More important, statin treatment is associated with reduction of endothelial dysfunction, oxidative stress and Rac-1 activation. Therefore, Rac-1 could represent the target of novel therapeutic strategies aimed to reduce vascular dysfunction in diabetes mellitus.