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Zimmer, Sebastian [Author]; Goody, Philip Roger [Author]; Oelze, Matthias [Author]; Ghanem, Alexander [Author]; Mueller, Cornelius F. [Author]; Laufs, Ulrich [Author]; Daiber, Andreas [Author]; Jansen, Felix [Author]; Nickenig, Georg [Author]; Wassmann, Sven [Author]

Inhibition of Rac1 GTPase Decreases Vascular Oxidative Stress, Improves Endothelial Function, and Attenuates Atherosclerosis Development in Mice

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  • Media type: E-Article
  • Title: Inhibition of Rac1 GTPase Decreases Vascular Oxidative Stress, Improves Endothelial Function, and Attenuates Atherosclerosis Development in Mice
  • Contributor: Zimmer, Sebastian [Author]; Goody, Philip Roger [Author]; Oelze, Matthias [Author]; Ghanem, Alexander [Author]; Mueller, Cornelius F. [Author]; Laufs, Ulrich [Author]; Daiber, Andreas [Author]; Jansen, Felix [Author]; Nickenig, Georg [Author]; Wassmann, Sven [Author]
  • Published: Lausanne: Frontiers Research Foundation, [2023]
  • Published in: Frontiers in Cardiovascular Medicine ; 8, (2021)
  • Language: English
  • Keywords: endothelial function ; oxidative stress ; Rac1 ; atherosclerosis ; free radicals ; GTPases
  • Origination:
  • Footnote:
  • Description: Aims: Oxidative stress and inflammation contribute to atherogenesis. Rac1 GTPaseregulates pro-oxidant NADPH oxidase activity, reactive oxygen species (ROS) formation,actin cytoskeleton organization and monocyte adhesion. We investigated the vasculareffects of pharmacological inhibition of Rac1 GTPase in mice.Methods and Results: We treated wild-type and apolipoprotein E-deficient (ApoE−/−)mice with Clostridium sordellii lethal toxin (LT), a Rac1 inhibitor, and assessedvascular oxidative stress, expression and activity of involved proteins, endothelialfunction, macrophage infiltration, and atherosclerosis development. LT-treated wild-typemice displayed decreased vascular NADPH oxidase activity and ROS production.Therapeutic LT doses had no impact on behavior, food intake, body weight, heartrate, blood pressure, vascular and myocardial function, differential blood count, andvascular permeability. ApoE−/− mice were fed a cholesterol-rich diet and weretreated with LT or vehicle. LT treatment led to decreased aortic Rac1 GTPaseactivity, NADPH oxidase activity and ROS production, but had no impact onexpression and membrane translocation of NADPH oxidase subunits and RhoA GTPaseactivity. LT-treated mice showed improved aortic endothelium-dependent vasodilation,attenuated atherosclerotic lesion formation and reduced macrophage infiltration ofatherosclerotic plaques. Concomitant treatment of cholesterol-fed ApoE−/− mice withLT, the specific synthetic Rac1 inhibitor NSC 23766 or simvastatin comparably reducedaortic Rac1 activity, NADPH oxidase activity, oxidative stress, endothelial dysfunction,atherosclerosis development, and macrophage infiltration.Conclusions: These findings identify an important role of the small GTPase Rac1 inatherogenesis and provide a potential target for anti-atherosclerotic therapy.
  • Access State: Open Access
  • Rights information: Attribution (CC BY)