Rac 1 modulates endothelial function and platelet aggregation in diabetes mellitus

Gabriele Giacomo Schiattarella, Albino Carrizzo, Federica Ilardi, Antonio Damato, Mariateresa Ambrosio, Michele Madonna, Valentina Trimarco, Marina Marino, Elena De Angelis, Silvio Settembrini, Cinzia Perrino, Bruno Trimarco, Giovanni Esposito, Carmine Vecchione

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish
Article numbere007322
JournalJournal of the American Heart Association
Volume7
Issue number8
DOIs
Publication statusPublished - Apr 17 2018

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Platelet Aggregation
Diabetes Mellitus
Blood Platelets
Pharmacology
Blood Vessels
rac1 GTP-Binding Protein
rho-Associated Kinases
rho GTP-Binding Proteins
Protein-Serine-Threonine Kinases
Platelet Aggregation Inhibitors
NADP
Hyperglycemia
Oxidoreductases
Oxidative Stress
Therapeutics
Morbidity
Mortality

Keywords

  • Cardiovascular disease
  • Endothelial dysfunction
  • NO
  • Oxidative stress
  • Vascular reactivity

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Rac 1 modulates endothelial function and platelet aggregation in diabetes mellitus. / Schiattarella, Gabriele Giacomo; Carrizzo, Albino; Ilardi, Federica; Damato, Antonio; Ambrosio, Mariateresa; Madonna, Michele; Trimarco, Valentina; Marino, Marina; Angelis, Elena De; Settembrini, Silvio; Perrino, Cinzia; Trimarco, Bruno; Esposito, Giovanni; Vecchione, Carmine.

In: Journal of the American Heart Association, Vol. 7, No. 8, e007322, 17.04.2018.

Research output: Contribution to journalArticle

Schiattarella, GG, Carrizzo, A, Ilardi, F, Damato, A, Ambrosio, M, Madonna, M, Trimarco, V, Marino, M, Angelis, ED, Settembrini, S, Perrino, C, Trimarco, B, Esposito, G & Vecchione, C 2018, 'Rac 1 modulates endothelial function and platelet aggregation in diabetes mellitus', Journal of the American Heart Association, vol. 7, no. 8, e007322. https://doi.org/10.1161/JAHA.117.007322
Schiattarella, Gabriele Giacomo ; Carrizzo, Albino ; Ilardi, Federica ; Damato, Antonio ; Ambrosio, Mariateresa ; Madonna, Michele ; Trimarco, Valentina ; Marino, Marina ; Angelis, Elena De ; Settembrini, Silvio ; Perrino, Cinzia ; Trimarco, Bruno ; Esposito, Giovanni ; Vecchione, Carmine. / Rac 1 modulates endothelial function and platelet aggregation in diabetes mellitus. In: Journal of the American Heart Association. 2018 ; Vol. 7, No. 8.
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AB - 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.

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