Title:Rac-1 as a New Therapeutic Target in Cerebro- and Cardio-Vascular Diseases
Volume: 15
Issue: 13
Author(s): Albino Carrizzo, Maurizio Forte, Maria Lembo, Luigi Formisano, Annibale A. Puca and Carmine Vecchione
Affiliation:
Keywords:
Rac-1, NSC23766, oxidative stress, NADPH oxidase, cardiovascular, cerebrovascular.
Abstract: Growing evidence indicates that overproduction of reactive oxygen species (ROS) plays a prominent role in the
development of cardio- and cerebro-vascular diseases. Among the mechanisms identified to produce oxidative stress in
the vascular wall, those mediated by membrane-bound NAD(P)H oxidases represent a major one. NAD(P)H oxidases are
a family of enzymes that generate ROS both in phagocytic and non-phagocytic cell types. Vascular NAD(P)H oxidase
contains the membrane-bound subunits Nox1, Nox2 (gp91phox), Nox4 and p22phox, the catalytic site of the oxidase, and
the cytosolic components p47phox and p67phox. Rac1 (Ras-related C3 botulinum toxin substrate1) is a small GTPase essential
for the assembly and activation of NADPH oxidase. Several molecular and cellular studies have reported the involvement
of Rac1 in different cardiovascular pathologies, such as vascular smooth muscle proliferation, cardiomyocyte
hypertrophy, endothelial cell shape change, atherosclerosis and endothelial dysfunction in hypertension. In addition, increased
activation of NADPH oxidase by Rac1 has been reported in animals and humans after myocardial infarction and
heart failure. The Rac1/NADPH pathway has also been found involved in different pathologies of the cerebral district,
such as ischemic stroke, cognitive impairment, subaracnoid hemorrhage and neuronal oxidative damage typical of several
neurodegenerative disorders. In addition, thrombotic events are an important step in the onset of cardio- and cerebrovascular
diseases. Rac1 has been found involved also in platelet activation, inducing actin polymerization and lamellipodia
formation, which are necessary steps for platelet aggregation. Taken together, the evidence candidates Rac1 as a new
pharmacological target of cardiovascular and cerebrovascular diseases. Although the involvement of Rac1 in the beneficial
pleiotropic effects of drugs such as statins is well known, and the onset of numerous side effects has raised concern
for the management of some patient groups. Interestingly, a novel selective Rac1 inhibitor, NSC23766, has recently been
introduced; its use has been reported mainly in the oncology field. Future studies are needed to extend its application to
cardio- and cerebro-vascular diseases, and translate its use to humans.
