Open AccessRac1 Modulates Endothelial Function and Platelet Aggregation in Diabetes Mellitus
Author(s) -
Schiattarella Gabriele Giacomo,
Carrizzo Albino,
Ilardi Federica,
Damato Antonio,
Ambrosio Mariateresa,
Madonna Michele,
Trimarco Valentina,
Marino Marina,
De Angelis Elena,
Settembrini Silvio,
Perrino Cinzia,
Trimarco Bruno,
Esposito Giovanni,
Vecchione Carmine
Publication year - 2018
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.117.007322
Subject(s) - medicine , diabetes mellitus , rac1 , platelet , nicotinamide adenine dinucleotide phosphate , platelet activation , pharmacology , oxidative stress , endothelial dysfunction , type 2 diabetes mellitus , endocrinology , biochemistry , signal transduction , oxidase test , biology , enzyme
Background Vascular complications and abnormal platelet function contribute to morbidity and mortality in diabetes mellitus. We hypothesized that the Rho‐related GTP ase 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 NSC 23766, a pharmacological inhibitor of Rac1, on vascular function in diabetic mice and platelet aggregation in diabetic subjects. We demonstrated that the administration of NSC 23766 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 NSC 23766 treatment. Finally, we characterized the antiplatelet effect of NSC 23766 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.