Department of Medicine, Division of Cardiology, Duke University Medical Center, Durham, North Carolina 27710
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ABSTRACT |
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small G proteins; antioxidants; atherosclerosis; NADPH oxidase
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The role of Rac as a regulator of the NADPH oxidase complex was first described in phagocytes, where the isoforms Rac1 and Rac2 control respiratory burst oxidation. Recently, an NADPH oxidase complex, regulated by Rac1, has been characterized in nonphagocytic cells, such as vascular smooth muscle, cardiac myocytes, and endothelial cells (for review, see Ref. 32). Rac-regulated production of superoxide by the nonphagocytic NADPH oxidase has proved to be a core element in the transduction of cardiovascular signals including angiotensin II (ANG II) (77, 81), PDGF (74), thrombin (85), endothelin (18), and leukotriene B4 (LTB4) (108) (Table 1). In contrast to phagocytes, nonphagocytic cells exhibit low-intensity basal production of superoxide, tightly controlled by Rac1, as well as small bursts of NADPH oxidase activity upon Rac1 stimulation. The control of redox-dependent cellular events represents a relatively new paradigm in cell signaling that has been recently reviewed (30, 49). We will highlight the importance of examining superoxide regulation by Rac, because the cross talk and spatial confinement that it confers may help explain the complex and sometimes contradictory finding with oxidant modulation.
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BIOCHEMICAL STRUCTURE AND FUNCTION |
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Individual GEFs, by possessing distinct lipid- and protein-binding motifs in addition to sites to bind Rac, seem to dictate which subset of a multitude of downstream effectors are targeted upon Rac activation (13, 23). For example, whereas GEF-independent activation of Rac stimulates both p21-activated kinase (PAK) and c-Jun NH2-terminal kinase (JNK) pathways, the Rac-specific GEF Tiam1 preferentially activates PAK, with minimal JNK activation (115). This bears physiological significance because PAK and JNK mediate distinct cellular events (cytoskeletal reorganization and gene expression, respectively). Thus, although Rac is always activated through a common pathway of GTP binding, the GEFs potentially allow diverse upstream signals to culminate in downstream cellular events that are equally diverse and specific.
Once bound to GTP, Rac is self-inactivated through slow intrinsic GTPase
activity, which is greatly enhanced by interaction with GAPs. The enhancement
is through a conserved GAP domain, found for example in N- and
-chimerins, that inserts into the active site of Rac to stabilize the
transition state and thus favors GTP hydrolysis
(10). In addition to
regulating the speed of GTP-GDP cycling, individual GAPs also contain unique
domains that mediate downstream effects. In fibroblasts, microinjection of N-
and
-chimerins, including mutants lacking GAP activity, induces
Rac-dependent lamellipodia formation
(46). In this sense, GAPs may
be viewed as a special set of Rac effector proteins, not only capable of
binding to activated Rac to transduce downstream signals but with the
additional ability to turn off their own upstream activation. Coordinated cell
function may also be facilitated by the ability of GAPs to inactivate multiple
members of the small G protein family, which occurs with p190 RhoGap.
Moreover, phosphorylated p190 can bind to the SH2 domain of the Ras-specific
GAP p150, producing cross talk between effector proteins
(82). In addition, more
complex molecules such as Bcr can exhibit both GEF activity for one small G
protein and GAP activity for another, allowing it to activate one pathway
while silencing another
(14).
In addition to domains for binding and hydrolyzing GTP, Rac activity also requires a COOH-terminal geranylgeranyl moiety. This modification, essential for the localization of Rac to the plasma membrane upon activation (73, 90), arises from posttranslational addition by the enzyme geranylgeranyl transferase (GGT) (12). Interestingly, geranylgeranyl groups, like cholesterol, are derived from the mevalonate pathway, and their production is blocked by HMG-CoA reductase inhibitors (statins) (73, 90). Thus modification of small G proteins by statins may contribute to their beneficial effect in cardiovascular disease (91). The geranylgeranyl moiety of inactive Rac can be sequestered within the hydrophobic pockets of GDIs. These cytosolic proteins stabilize both GDP- and GTP-bound Rac to prevent unnecessary GTP cycling and inhibit inactive Rac from interacting with effector proteins, such as PAK, through concealment of key structural regions (24). Live cell imaging has revealed that proper cellular localization of Rac is crucial because certain effector molecules, such as PAK, bind to Rac only after successful membrane targeting (47). However, GDI-mediated presentation of Rac to other effectors, such as the p67phox component of the NADPH oxidase complex, appears to occur in the cytosol (17, 22).
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RAC AND NADPH OXIDASE REGULATION |
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Interestingly, the affinity of Rac for the oxidase differs depending on which GEF is bound to Rac. In COS cells engineered to express the oxidase components Gp91phox, p22phox, p47phox, and p67phox, a constitutively active Vav1 GEF mutant exhibits greater superoxide production than active Vav2 or Tiam1 mutants, despite greater PAK binding by the Vav2 and Tiam1 mutant (68) (Fig. 3). The importance of Rac GEFs in differentially regulating the activation of the oxidase in human disease is illustrated in oncogenic transformation, where the same NH2-terminal deletion of Vav1 used to create constitutively active mutants acts as a protooncogene (43). Inherited defects in Rho family GEFs have been identified recently in faciogenital dysplasia and X-linked mental retardation (48, 63). Although a cardiovascular disease related to polymorphism in Rac or Rac GEFs has yet to be identified, subtle genetic variations resulting from Rac and Rac GEF polymorphisms may potentially shift the Rac balance between different effectors to impact predisposition to cardiovascular disease.
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RAC ACTIVATION BY SURFACE RECEPTORS |
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RAC ACTIVATION BY RECEPTOR TYROSINE KINASES |
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RAC ACTIVATION BY ANG II |
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ANG II signaling proceeds through a heterotrimeric G protein-coupled receptor through both a Gq/11 pathway and a Gi pathway (94) (Fig. 5). With two parallel pathways resulting in Rac activation through the same receptor, investigations attempting to define the signaling requirements of each pathway have been complicated by the possibility of redundant pathways. Subtle differences in agonist dosing and kinetics also appear to produce different effects and may explain the seemingly contradictory investigations exploring the signal transduction pathways seen by Schmitz et al. (77) in contrast to Seshiah et al. (81). The most comprehensive model of ANG II activation of Rac and superoxide derives from work by Ushio-Fukai et al. (96) and Seshiah et al. (81). They propose that AT1 receptor binding leads to initial PKC activation, which directly results in rapid early reactive oxygen species (ROS) production. Sustained superoxide then proceeds through transactivation of the epidermal growth factor receptor (EGFR) by a Src kinase activated by the initial ROS burst. EGF subsequently activates PI3K with resultant activation of the small GTP-binding protein Rac, a key regulator of the NADPH oxidase complex, to result in long-term superoxide production. This model is well supported by their data, showing that inhibition of PKC with GF-109203x significantly blocks hydrogen peroxide production. Additionally, Src kinase appears to be activated by superoxide to transactivate the EGFR, because antioxidant treatment with diphenylene iodonium, an inhibitor of flavin oxidases, tiron, a superoxide scavenger, N-acetylcysteine, or ebselen, a glutathione peroxidase mimetic, will block both ANG II-induced EGFR and Src activation, whereas hydrogen peroxide treatment or treatment with the superoxide-releasing compound LY-83583 will mimic ANG II-induced EGFR phosphorylation. Similarly, inhibition of Src with protein phosphatase 1 (PP1) blocks EGFR activation and limits Rac-PAK binding and superoxide production. Further supporting this model, inhibition of EGFR kinase with AG-1478 or PI3K inhibition with wortmannin attenuated Rac-PAK binding (81, 96). In contrast, Schmitz et al. (77) found that ANG II induction of Rac activity as measured by PAK-PBD binding is inhibited by the global RTK inhibitor genistein but not the Src kinase inhibitor PP1, suggesting that activation requires a non-Src tyrosine kinase. Furthermore, although they found that activation also requires PKC, because downregulation of PKCs with the inhibitor phorbol 12,13-dibutyrate limits Rac-PAK binding, the low-dose PKC inhibitor GF-109203x had only minimal effect (77). The precise explanation for these apparently contradictory findings is unclear. Furthermore, Seshiah et al. (81) found that early PKC-derived superoxide precedes Rac activation by EGFR transactivation; however, whether this initial NADPH oxidase activation through PKC involves Rac as well remains unclear. In their different model system, Schmitz et al. (77) show Rac-PAK binding 15 s after stimulation, whereas EGFR transactivation has not been shown earlier than 1 min, suggesting perhaps that Rac is directly activated to effect the early superoxide burst and later activated through EGFR to perpetuate a more sustained activation.
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RAC IN CARDIOVASCULAR DISEASE |
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Cardiac hypertrophy. Myocardial hypertrophy can be an adaptive, or
maladaptive, response to increased wall stress resulting from chronic
hypertension or altered cardiac geometry after myocardial infarction;
furthermore, excessive hypertrophy leads to impaired myocardial function and
eventual heart failure. In addition to potentially promoting cytoskeletal and
myofibrillar rearrangement, Rac also contributes to myocardial hypertrophy by
activation of cellular growth pathways
(19). Hyperactivation of
growth signals underlies the oncogenic effects of Rac in mitotically competent
cells (41), whereas similar
activation in postmitotic cells, such as cardiomyocytes, appears to result in
a hypertrophic phenotype. In investigations of this analogy, early evidence of
the role of Rac in oncogenic transformation and the regulation of important
pathways controlling genes involved in growth and proliferation, such as p38
mitogen-activated kinase (MAPK), JNK, Akt, and ERK, sparked interest in a
possible role of Rac in cardiac hypertrophy. Similarly, Rac GEFs, such as Vav
and Sos, had been observed to be involved in oncogenesis, further suggesting
that Rac and its associated GEFs might be involved in cardiac hypertrophy.
Subsequent work positioned Rac and superoxide as a necessary downstream signal
of the small G protein Ras, a key regulator of mitogenesis and oncogenic
transformation (41,
69), and in neonatal
cardiomyocytes, adenoviral infection with a dominant negative form of Ras
blunts the activation of MAPK, suggesting a possible relationship of Rac in
cardiac hypertrophy (66).
These findings were subsequently extended to directly implicate Rac when it
was shown in neonatal rat cardiomyocytes that constitutively active Rac V12
induced sarcomeric reorganization and hypertrophy indistinguishable from
phenylephrine-induced changes. Rac also resulted in increased expression of
the embryonic gene atrial natriuretic peptide. Furthermore, dominant negative
Rac N17 blocks phenylephrine-induced hypertrophic changes
(67). In vitro work has
continued to implicate Rac as a messenger of other important hypertrophic
pathways including signal transduction downstream of ANG II, TNF-, and
EGF. Finally, a mouse model in which a constitutively active Rac V12 gene was
expressed selectively in the myocardium confirms that Rac activation leads to
cardiac hypertrophy in vivo. These transgenic mice show two phenotypes: a
lethal dilated cardiomyopathy associated with neonatal expression, and a
viable hypertrophy in young mice that resolved with age. Interestingly,
excessive Rac activation did not lead to any myofibrillary derangement, and
Rac V12 hearts were in fact hypercontractile
(87).
Although PAK binding has been used to document increased Rac activation in cardiac hypertrophy, the downstream effector most likely mediating Rac-induced hypertrophy is superoxide produced by NADPH oxidase. By infection of fibroblasts with PAK mutants unable to bind Rac, Westwick et al. (106) showed that Rac-induced mitogenesis, transformation, and lamellipodia formation as well as activation of growth-related genes JNK, p38, and serum response factor (SRF) are PAK independent. Hinting that Rac-activated NADPH oxidase is the critical mediator of hypertrophy, EGF-induced calcium release in fibroblasts correlates with hydrogen peroxide production and can be blocked by dominant negative Rac or the antioxidant enzyme catalase (52). In addition, catalase and SOD mimetics also blunt mechanical stress-induced hypertrophy and activation of JNK and ERK in cardiomyocytes (65). These findings provide a mechanism by which Rac activation by ANG II can induce cardiac hypertrophy independent of blood pressure elevation (77), through increased superoxide generation (9). Indeed, ANG II-induced hypertrophy is blunted by the Rac inhibitor C3 exotoxin as well as dominant negative Rac and SOD (92). Furthermore, statins, in addition to their cholesterol-lowering effects, may also regulate cardiac hypertrophy by inhibiting Rac prenylation and oxidant signaling (51, 92). Treatment of rat cardiomyocytes with simvastatin in vitro blocks ANG II-induced hypertrophy and fetal gene expression, which correlates with decreased Rac activity and superoxide production. Convincingly, simvastatin also inhibits cardiac hypertrophy in rats treated with either ANG II or transaortic constriction, which is associated with a concomitant decrease in myocardial Rac activity and superoxide production in vivo (92).
Vascular hypertrophy. Vascular remodeling is a compensatory response to vascular insults such as hypertension and increased sheer stress and is implicated in the development of atherosclerosis. Evidence supporting the role of Rac in vascular hypertrophy stems from its role in regulating gene expression, controlling superoxide production, and sensing and transducing shear stress. Although the upstream signals are yet unidentified, Rac is activated by vascular shear stress, resulting in transduction of growth and hypertrophy signals. In vascular smooth muscle cells (VSMC), dominant negative Rac N17 blocks cyclic strain-induced activation of p38 MAPK and ERK (53, 54). Not surprisingly, this regulation appears to be superoxide dependent, with shear-induced MAPK activation equally blocked by antioxidants or RacDN (111). Heat shock protein expression and activation in response to both cyclic stress and heat stress also require Rac (110). As in cardiac hypertrophy, Rac is essential for ANG II-induced vascular remodeling, with ANG II Rac-dependently activating ERK and JNK pathways in VSMC (77). In addition, vascular NADPH oxidase components are upregulated in vivo upon ANG II infusion (15, 29). Furthermore, ANG II-induced vascular hypertrophy is blocked by catalase, SOD mimetics, and antisense p22phox cDNA in vitro (97, 113) or by knockout of gp91phox in mice (102).
Hypertension. There has been intense interest in the role of superoxide and oxidative stress in hypertension (114), because as both a key regulator of NADPH-derived superoxide and as a mediator of the potent vasoconstrictor ANG II, Rac is likely an important regulatory target in hypertension. Illustrating the importance of Rac-derived superoxide, angiotensin treatment results in increased superoxide production with significantly increased membrane-bound NADH and NADPH oxidase. Impaired relaxation to calcium ionophore, acetylcholine, and nitroglycerin are also seen after ANG II treatment, and these changes can be reversed with an SOD mimetic (71). Direct inhibition of the oxidase in a mouse model with a chimeric protein gp91ds-tat, which inhibits the interaction of p47phox and gp91phox, or use of p47phox knockout mice blunts the superoxide production and hypertension induced by ANG II treatment and clearly demonstrates that in vivo NADPH oxidase-produced superoxide is the essential mediator of angiotensin's hypertensive response (50, 72). Interestingly, the spontaneous hypertensive rat (SHR) shows enhanced superoxide production with increased expression of the oxidase component p22 and impaired vasodilatation to acetylcholine (29). Moreover, treating normocholesterolemia SHR with statins reduces blood pressure with a concomitant decrease in superoxide production as well as angiotensin receptor NADPH oxidase component expression (104). Mechanistically, Rac-derived superoxide production may act as an antagonist to vasodilatory nitric oxide (NO) through the rapid reaction of the two reactive species to form peroxynitrite, thus decreasing NO bioactivity (114).
Rac has now been directly implicated in hypertension in vivo through the
development of a transgenic mouse model expressing constitutively active
RacV12 under an -actin promoter for smooth muscle-selective expression.
These mice show hypertension compared with wild-type littermates, caused by
enhanced superoxide production. Treatment of these mice with the antioxidant
N-acetylcysteine results in reversal of the hypertension
(Goldschmidt-Clermont, unpublished data). Similarly, Rac mediates the
arteriolar constriction response to increased transmural wall pressure. In
studies using isolated mouse tail arterioles, increased wall pressure has been
shown to result in superoxide production and arteriolar contraction that could
be attenuated with RacDN or superoxide inhibition
(62).
Atherosclerosis. There has long been interest in the role of oxidative stress and antioxidants in the development of atherosclerosis. Recently, it was shown that cellular oxidative stress predicts mortality in patients with coronary artery disease (37). Smooth muscle cells from p47phox-/- knockout mice lacking a key component of the oxidase exhibit decreased proliferation and superoxide production. Furthermore, knockout of p47phox attenuates the development of atherosclerosis in ApoE-/- mice (8). As the core regulator of superoxide production through the NAD(P)H oxidase, Rac is positioned as a critical atherogenic signal. In mice, Rac appears to be directly linked to the consequences of hypercholesterolemia, which include increased NADPH-derived superoxide production, increased expression of the AT1 receptor, and impaired endothelium-dependent vasorelaxation. In addition, hypercholesterolemic mice have increased macrophage infiltration of the vasculature and enhanced plaque rupture that are attenuated with AT1 receptor antagonism (103). Similarly, in vascular injury resulting from balloon-induced carotid injury, there is a significant upregulation of the oxidase component Nox1 with associated increased superoxide production, pointing to a central role of NADPH oxidase-generated superoxide in restenosis (89). Coordinated Rac activity may also be important in smooth muscle migration from the media to intima required for the development of atherosclerosis, because both Ra N17 and, to a lesser extent, RacV12 inhibit smooth muscle migration (26). Similarly, endothelial migration and cytoskeletal changes controlling the integrity of the vascular wall are regulated by Rac and superoxide (60). Moreover, because Rac activation requires geranylgeranyl synthesis, which is inhibited by statins, Rac deactivation may account for the cholesterol-independent antiatherosclerotic effects of statins demonstrated in clinical trials (57, 91). In addition to lowering cholesterol, statins limit smooth muscle cell hypertrophy and vascular inflammation, improve vasoreactivity, stabilize plaques, and regulate platelet aggregation all through pathways that appear to be regulated by Rac and Rho family GTPases (91). Moreover, in VSMC, atorvastatin blocks ANG II-induced Rac activation and downstream superoxide production, an effect that is mimicked by GGT inhibitors and reversed by mevalonate (105). Interestingly, in contrast, treatment of endothelial cells with cerivastatin increases Rac activation as measured by Rac-PAK binding in total cell lysates, although statin treatment decreases the fraction of Rac that was membrane localized (100).
Atherosclerotic vessels also demonstrate reduced levels of NO, which may be mediated by NO inactivation by superoxide to produce peroxynitrite. In vivo investigations in hypercholesterolemic rabbits demonstrate statin inhibition of Rac and superoxide with resultant restoration of NO levels and plaque stabilization (93). Moreover, Rac activity enhances the expression of plaque-destabilizing cytokines such as IL-6 and monocyte chemoattractant protein (MCP-1) through superoxide (28, 56). In fact, Rac-dependent MCP-1 expression is blocked by NO, suggesting an inactivation of Rac-derived superoxide by NO (109).
Leukocyte migration, chemotaxis, and platelet aggregation. Communication of the vasculature with both leukocytes and platelets is crucial in the vascular flux of inflammatory cells leading to both chronic atherosclerosis and acute thrombus formation. Rac signaling is central to leukocyte attraction, migration, and vascular attachment via production of MCP-1, regulation of cellular motility, and expression of adhesion molecules. In addition to shear stress-induced endothelial injury that summons leukocytes, Rac also contributes to the cytoskeletal rearrangement necessary for the movement of inflammatory cells through the endothelium (42, 76). Both dominantly negative and constitutively active Rac inhibit macrophage migration (5, 42) and PDGF-induced chemotaxis of fibroblasts and VSMC. The ability of both the dominant negative and constitutively active Rac to inhibit these processes indicates that a balanced, coordinated regulation of Rac is necessary to regulate cell movement. The potent chemoattractant LTB4 also activates Rac and ROS production (108), and blockade of the leukocyte LTB4 receptor attenuates atherosclerosis in mice by diminishing monocytic infiltration of the vasculature (3).
In platelets, thrombin signaling and interaction with adhesion molecules
requires Rac and contributes to subsequent thrombus formation
(85). Cytoskeletal
reorganization is necessary for platelet activation and morphological changes
(34,
35). Rac and PAK are activated
in the process of platelet spreading on collagen through a pathway that
requires Src kinase and, to a lesser extent, PI3K. This appears to be
independent of integrin 2
1, because surfaces coated with
anti-
2
1 also induce Rac binding of PAK with a requirement of Src
and PI3K (88). Through the use
of PAK binding assays, thrombin, which signals through a heterotrimeric G
protein coupled receptor, and collagen, which signals through an RTK, have now
both been demonstrated to rapidly activate Rac with the requirement of
phospholipase C and calcium mobilization. Activation by collagen also requires
PI3K, whereas thrombin is PI3K independent
(85). Interestingly, integrins
appear to predominantly regulate Rac activation not through effects on GTP
loading but, rather, through the plasma membrane localization of Rac that is
already GTP bound. Transfection of cells with V12 Rac does not result in
global PAK binding but, rather, is limited to specific plasma membrane locales
where integrin activation is occurring. Thus integrins provide spatiotemporal
regulation of Rac's binding to effectors, which appears to be mediated by GDI
release (24).
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FUTURE |
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DISCLOSURES |
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Address for reprint requests and other correspondence: P. J.
Gold-schmidt-Clermont, Dept. of Medicine, Duke Univ. Medical Center, Durham,
NC 27710 (E-mail:
golds017{at}mc.duke.edu).
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