TY - JOUR
T1 - Rac1 Pharmacological Inhibition Rescues Human Endothelial Dysfunction
AU - Carrizzo, Albino
AU - Vecchione, Carmine
AU - Damato, Antonio
AU - di Nonno, Flavio
AU - Ambrosio, Mariateresa
AU - Pompeo, Franco
AU - Cappello, Enrico
AU - Capocci, Luca
AU - Peruzzi, Mariangela
AU - Valenti, Valentina
AU - Biondi-Zoccai, Giuseppe
AU - Marullo, Antonino G M
AU - Palmerio, Silvia
AU - Carnevale, Roberto
AU - Spinelli, Chiara C
AU - Puca, Annibale A
AU - Rubattu, Speranza
AU - Volpe, Massimo
AU - Sadoshima, Junichi
AU - Frati, Giacomo
AU - Sciarretta, Sebastiano
N1 - © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
PY - 2017/2/28
Y1 - 2017/2/28
N2 - BACKGROUND: Endothelial dysfunction contributes significantly to the development of vascular diseases. However, a therapy able to reduce this derangement still needs to be identified. We evaluated the effects of pharmacological inhibition of Rac1, a small GTPase protein promoting oxidative stress, in human endothelial dysfunction.METHODS AND RESULTS: We performed vascular reactivity studies to test the effects of NSC23766, a Rac1 inhibitor, on endothelium-dependent vasorelaxation of saphenous vein segments collected from 85 subjects who had undergone surgery for venous insufficiency and from 11 patients who had undergone peripheral vascular surgery. The endothelium-dependent vasorelaxation of the varicose segments of saphenous veins collected from patients with venous insufficiency was markedly impaired and was also significantly lower than that observed in control nonvaricose vein tracts from the same veins. Rac1 activity, reactive oxygen species levels, and reduced nicotine adenine dinucleotide phosphate (NADPH) oxidase activity were significantly increased in varicose veins, and NSC23766 was able to significantly improve endothelium-dependent vasorelaxation of dysfunctional saphenous vein portions in a nitric oxide-dependent manner. These effects were paralleled by a significant reduction of NADPH oxidase activity and activation of endothelial nitric oxide synthase. Finally, we further corroborated this data by demonstrating that Rac1 inhibition significantly improves venous endothelial function and reduces NADPH oxidase activity in saphenous vein grafts harvested from patients with vascular diseases undergoing peripheral bypass surgery.CONCLUSIONS: Rac1 pharmacological inhibition rescues endothelial function and reduces oxidative stress in dysfunctional veins. Rac1 inhibition may represent a potential therapeutic intervention to reduce human endothelial dysfunction and subsequently vascular diseases in various clinical settings.
AB - BACKGROUND: Endothelial dysfunction contributes significantly to the development of vascular diseases. However, a therapy able to reduce this derangement still needs to be identified. We evaluated the effects of pharmacological inhibition of Rac1, a small GTPase protein promoting oxidative stress, in human endothelial dysfunction.METHODS AND RESULTS: We performed vascular reactivity studies to test the effects of NSC23766, a Rac1 inhibitor, on endothelium-dependent vasorelaxation of saphenous vein segments collected from 85 subjects who had undergone surgery for venous insufficiency and from 11 patients who had undergone peripheral vascular surgery. The endothelium-dependent vasorelaxation of the varicose segments of saphenous veins collected from patients with venous insufficiency was markedly impaired and was also significantly lower than that observed in control nonvaricose vein tracts from the same veins. Rac1 activity, reactive oxygen species levels, and reduced nicotine adenine dinucleotide phosphate (NADPH) oxidase activity were significantly increased in varicose veins, and NSC23766 was able to significantly improve endothelium-dependent vasorelaxation of dysfunctional saphenous vein portions in a nitric oxide-dependent manner. These effects were paralleled by a significant reduction of NADPH oxidase activity and activation of endothelial nitric oxide synthase. Finally, we further corroborated this data by demonstrating that Rac1 inhibition significantly improves venous endothelial function and reduces NADPH oxidase activity in saphenous vein grafts harvested from patients with vascular diseases undergoing peripheral bypass surgery.CONCLUSIONS: Rac1 pharmacological inhibition rescues endothelial function and reduces oxidative stress in dysfunctional veins. Rac1 inhibition may represent a potential therapeutic intervention to reduce human endothelial dysfunction and subsequently vascular diseases in various clinical settings.
KW - Adolescent
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Aminoquinolines/pharmacology
KW - Chronic Disease
KW - Endothelium, Vascular/drug effects
KW - Female
KW - Humans
KW - Immunoblotting
KW - Male
KW - Middle Aged
KW - NADP/metabolism
KW - Nitric Oxide Synthase Type III/metabolism
KW - Oxidative Stress/drug effects
KW - Pyrimidines/pharmacology
KW - Reactive Oxygen Species/metabolism
KW - Saphenous Vein/drug effects
KW - Vasodilation/drug effects
KW - Venous Insufficiency/metabolism
KW - Young Adult
KW - rac1 GTP-Binding Protein/antagonists & inhibitors
U2 - 10.1161/JAHA.116.004746
DO - 10.1161/JAHA.116.004746
M3 - Article
C2 - 28246076
VL - 6
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
SN - 2047-9980
IS - 3
ER -