Rac regulates cardiovascular superoxide through diverse molecular interactions: more than a binary GTP switch.
The small G protein Rac has been implicated in multiple cardiovascular processes. Rac has two major functions: 1) it regulates the organization of the actin cytoskeleton, and 2) it controls the activity of the key enzyme complex NADPH oxidase to control superoxide production in both phagocytes and nonphagocytic cells. In phagocytes, superoxide derived from NADPH has a bactericidal function, whereas Rac-derived superoxide in the cardiovascular system has a diverse array of functions that have recently been a subject of intense interest. Rac is differentially activated by cellular receptors coupled to distinct Rac-activating adapter molecules, with each leading to pathway-specific arrays of downstream effects. Thus it may be important to investigate not just whether Rac is activated but also where, how, and for what effector. An understanding of the biochemical functions of Rac and its effectors lays the groundwork for a dissection of the exact array of effects produced by Rac in common cardiovascular processes, including cardiac and vascular hypertrophy, hypertension, leukocyte migration, platelet biology, and atherosclerosis. In addition, investigation of the spatiotemporal regulation of both Rac activation and consequent superoxide generation may produce new insights into the development of targeted antioxidant therapies for cardiovascular disease and enhance our understanding of important cardiovascular drugs, including angiotensin II antagonists and statins, that may depend on Rac modulation for their effect.
Gregg
David
D
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Rauscher
Frederick M
FM
Goldschmidt-Clermont
Pascal J
PJ
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D002318:Cardiovascular Diseases / Q000378:metabolism; D002319:Cardiovascular System / Q000378:metabolism*; D006801:Humans; D019255:NADPH Oxidases / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism*
D011956:Receptors, Cell Surface; D013481:Superoxides; D000804:Angiotensin II; D019255:NADPH Oxidases; D020794:Receptor Protein-Tyrosine Kinases; D020744:rac GTP-Binding Proteins