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Rac1 modulates endothelial function and platelet aggregation in diabetes mellitus

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Item Type:Article
Title:Rac1 modulates endothelial function and platelet aggregation in diabetes mellitus
Creators Name:Schiattarella, G.G. and Carrizzo, A. and Ilardi, F. and Damato, A. and Ambrosio, M. and Madonna, M. and Trimarco, V. and Marino, M. and De Angelis, E. and Settembrini, S. and Perrino, C. and Trimarco, B. and Esposito, G. and Vecchione, C.
Abstract:BACKGROUND: Vascular complications and abnormal platelet function contribute to morbidity and mortality in diabetes mellitus. We hypothesized that the Rho-related GTPase protein, Rac1, can influence both endothelial and platelet function and might represent a potential novel therapeutic target in diabetes mellitus. METHODS AND RESULTS: We used both in vitro and ex vivo approaches to test the effects of pharmacological inhibition of Rac1 during hyperglycemic condition. We evaluated the effect of NSC23766, a pharmacological inhibitor of Rac1, on vascular function in diabetic mice and platelet aggregation in diabetic subjects. We demonstrated that the administration of NSC23766 protects from hyperglycemia-induced endothelial dysfunction, restoring NO levels, and reduces oxidative stress generated by nicotinamide adenine dinucleotide phosphate oxidase. Mechanistically, we identified Rho-associated coiled-coil serine/threonine kinase-1 as a downstream target of Rac1. Moreover, we reported that during hyperglycemic conditions, human platelets showed hyperactivation of Rac1 and impaired NO release, which were both partially restored after NSC23766 treatment. Finally, we characterized the antiplatelet effect of NSC23766 during hyperglycemic conditions, demonstrating the additional role of Rac1 inhibition in reducing platelet aggregation in diabetic patients treated with common antiplatelet drugs. CONCLUSIONS: Our data suggest that the pharmacological inhibition of Rac1 could represent a novel therapeutic strategy to reduce endothelial dysfunction and platelet hyperaggregation in diabetes mellitus.
Keywords:Endothelial Dysfunction, NO, Oxidative Stress, Cardiovascular Disease, Vascular Reactivity, Animals, Mice
Source:Journal of the American Heart Association
Page Range:e007322
Date:17 April 2018
Official Publication:https://doi.org/10.1161/JAHA.117.007322
PubMed:View item in PubMed

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