title: Rac1 Pharmacological Inhibition Rescues Human Endothelial Dysfunction.
abstract: 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.
  
  
  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.
authors.affiliation: IRCCS Neuromed, Pozzilli (IS), Italy.
authors.forename: Albino
authors.initials: A
authors.lastname: Carrizzo
authors.affiliation: IRCCS Neuromed, Pozzilli (IS), Italy cvecchione@unisa.it.|Department of Medicine and Surgery, University of Salerno, Baronissi (SA), Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Vecchione
authors.affiliation: IRCCS Neuromed, Pozzilli (IS), Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Damato
authors.affiliation: IRCCS Neuromed, Pozzilli (IS), Italy.
authors.forename: Flavio
authors.initials: F
authors.lastname: di Nonno
authors.affiliation: IRCCS Neuromed, Pozzilli (IS), Italy.
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Ambrosio
authors.affiliation: IRCCS Neuromed, Pozzilli (IS), Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Pompeo
authors.affiliation: IRCCS Neuromed, Pozzilli (IS), Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Cappello
authors.affiliation: IRCCS Neuromed, Pozzilli (IS), Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Capocci
authors.affiliation: Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome Polo Pontino, Latina, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Peruzzi
authors.affiliation: Department of Imaging, Bambino Gesù Children Hospital, IRCCS, Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Valenti
authors.affiliation: IRCCS Neuromed, Pozzilli (IS), Italy.|Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome Polo Pontino, Latina, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Biondi-Zoccai
authors.affiliation: Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome Polo Pontino, Latina, Italy.
authors.forename: Antonino G M
authors.initials: AG
authors.lastname: Marullo
authors.affiliation: Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome Polo Pontino, Latina, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Palmerio
authors.affiliation: Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome Polo Pontino, Latina, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Carnevale
authors.affiliation: IRCCS Multimedica S.p.A, Milan, Italy.
authors.forename: Chiara C
authors.initials: CC
authors.lastname: Spinelli
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Baronissi (SA), Italy.|IRCCS Multimedica S.p.A, Milan, Italy.
authors.forename: Annibale A
authors.initials: AA
authors.lastname: Puca
authors.affiliation: IRCCS Neuromed, Pozzilli (IS), Italy.|Department of Clinical and Molecular Medicine, Sapienza University of Rome, Italy.
authors.forename: Speranza
authors.initials: S
authors.lastname: Rubattu
authors.affiliation: IRCCS Neuromed, Pozzilli (IS), Italy.|Department of Clinical and Molecular Medicine, Sapienza University of Rome, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Volpe
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, NJ.
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
authors.affiliation: IRCCS Neuromed, Pozzilli (IS), Italy.|Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome Polo Pontino, Latina, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Frati
authors.affiliation: IRCCS Neuromed, Pozzilli (IS), Italy.|Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome Polo Pontino, Latina, Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Sciarretta
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000634:Aminoquinolines / Q000494:pharmacology*; D002908:Chronic Disease; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D006801:Humans; D015151:Immunoblotting; D008297:Male; D008875:Middle Aged; D009249:NADP / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012501:Saphenous Vein / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D014664:Vasodilation / Q000187:drug effects*; D014689:Venous Insufficiency / Q000378:metabolism / Q000503:physiopathology*; D055815:Young Adult; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
chemical_list: D000634:Aminoquinolines; C487513:NSC 23766; D011743:Pyrimidines; C107953:RAC1 protein, human; D017382:Reactive Oxygen Species; D009249:NADP; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D020830:rac1 GTP-Binding Protein
keywords: cardiovascular disease; endothelial dysfunction; nitric oxide; oxidative stress