Published online before print May 13, 2004, doi: 10.1161/01.ATV.0000132400.25045.2a
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© 2004 American Heart Association, Inc.
Vascular Biology |
Microtubules Regulate Angiotensin II Type 1 Receptor and Rac1 Localization in Caveolae/Lipid Rafts
Role in Redox Signaling
From the Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Ga.
Correspondence to Masuko Ushio-Fukai, PhD, Division of Cardiology, Emory University School of Medicine, 1639 Pierce Drive, Room 319, Atlanta, GA 30322. E-mail mfukai{at}emory.edu
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Abstract |
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Objective— Microtubules are important in signal transduction temporal–spatial organization. Full expression of angiotensin II (Ang II) signaling in vascular smooth muscle cells (VSMCs) is dependent on the reactive oxygen species (ROS) derived from nicotinamide-adenine dinucleotide phosphate (NAD(P)H) oxidase and the dynamic association of the Ang II type 1 receptor (AT1R) with caveolae/lipid rafts. Translocation of the small GTPase Rac1 to the plasma membrane is an essential step for activation of NAD(P)H oxidase; however, its precise localization in the plasma membrane after agonist stimulation and how it is targeted are unknown. We hypothesized that microtubules are involved in regulating multiphasic Ang II signaling events in VSMC.
Methods and Results— We show that Ang II promotes Rac1 and AT1R trafficking into caveolae/lipid rafts, which is blocked by disruption of microtubules with nocodazole. As a consequence, nocodazole significantly inhibits Ang II–stimulated H2O2 production, its downstream ROS-dependent epidermal growth factor receptor transactivation, Akt phosphorylation, and vascular hypertrophy without affecting Rac1 activation or ROS-independent extracellular signal-regulated kinase 1/2 phosphorylation.
Conclusions— These results suggest that proper Rac1 and AT1R trafficking into caveolae/lipid rafts requires the integrity of microtubules and provide insight into the essential role of microtubules for the spatial–temporal organization of ROS-dependent and caveolae/lipid rafts–dependent AT1R signaling linked to vascular hypertrophy.
The role of microtubules in angiotensin II (Ang II) signaling remains unknown. We demonstrate that Ang II promotes Rac1 and Ang II type 1 receptor trafficking into the caveolae/lipid rafts, which requires the integrity of microtubules. We also found that intact microtubules mediate Ang II–stimulated H2O2 production, its downstream EGF-R transactivation, Akt phosphorylation, and vascular hypertrophy.
Key Words: microtubules • angiotensin II • reactive oxygen species • caveolae • vascular smooth muscle
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Introduction |
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Microtubules play an important role in membrane trafficking and signal transduction temporal–spatial organization by serving as tracks for rapid movement of signaling molecules among subcellular compartments.1 Angiotensin II (Ang II) is a hypertrophic hormone and induces transactivation of the epidermal growth factor receptor (EGF-R). In turn, EGF-R serves as a scaffold for assembling signaling molecules such as mitogen-activated protein kinases and Akt that are important for the expression of the full Ang II type 1 receptor (AT1R) signaling repertoire in vascular smooth muscle cells (VSMCs).2–4 We and others have reported that these responses are mediated, in part, through reactive oxygen species (ROS) derived from nicotinamide-adenine dinucleotide phosphate (NAD(P)H) oxidase.4–6 The small GTPase Rac1 has been shown to be a key element in activation of NAD(P)H oxidase by Ang II in VSMCs.7 Translocation of Rac1 from the cytosol to the plasma membrane is an essential step for this process.8,9 Recently, microtubules were shown to be involved in mechanical stress-induced Rac1 translocation to the plasma membrane in VSMCs.10 We hypothesize that microtubules may be important in temporal and spatial organization of ROS-dependent Ang II signaling in VSMCs.
Lipid rafts and caveolae are organized plasma membrane microdomains that are enriched in cholesterol and sphingolipids and that can be isolated as low-density buoyant membranes in the absence of detergents.11,12 Caveolin-1 acts as a scaffolding protein to concentrate signaling molecules such as Src, H-Ras, and EGF-R in caveolae in the basal state.12,13 In contrast, some signaling molecules, including S-nitroso-N-acetylpenicillamine (SNAP)-2314 and phosphatidylinositol 4-kinase,15 localize at least basally in noncaveolae lipid rafts. Importantly, it has been suggested that microtubules are involved in caveolae-mediated membrane trafficking.16 We have shown that after activation, the AT1R moves into a caveolin-enriched fraction and associates with caveolin-1,17 and that caveolae-like microdomains are essential for transactivation of EGF-R by Ang II in VSMCs.3 Mechanisms by which AT1R is targeted to internalization pathways and its functional consequences are undefined. Recently, Nox1, a homolog of the phagocytic NAD(P)H oxidase subunit gp91phox, has been shown to be found in caveolin-enriched fractions in VSMCs.18 Several reports demonstrate that Rac1, which contains a caveolin-binding consensus sequence,13 is basally concentrated in caveolae;19,20 however, its precise localization in the plasma membrane before and after agonist stimulation and how it is regulated in VSMCs remain unclear.
We tested the hypothesis that increased plasma membrane association of Rac1 on Ang II stimulation might, at least in part, reflect localization in caveolae/lipid rafts. Furthermore, we investigated the role of microtubules in the Ang II–stimulated movement of Rac1 and AT1R as well as in its downstream ROS-dependent signaling events linked to vascular hypertrophy. The present study suggests that Ang II promotes Rac1 and AT1R trafficking into caveolae/lipid rafts via the microtubule network and provides insight into an essential role of microtubules for spatial–temporal organization of redox-sensitive, hypertrophy-related AT1R signaling in VSMCs.
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Methods |
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Methods are described in the online supplement (available at http://atvb.ahajournals.org).
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Results |
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To test whether Ang II–stimulated movement of Rac1 to plasma membranes involves caveolae, we performed detergent-free density OptiPrep gradient cell fractionation to isolate caveolae/lipid rafts.21 As shown in Figure 1A, Western blot analysis of sequential fractions from the gradient showed that the majority of Rac1 was found in heavier-density, noncaveolar membrane fractions (fractions 5 to 7) in unstimulated VSMCs. Ang II stimulation (5 minutes) moved Rac1 into buoyant, lower-density fractions,3–5 including some of those containing caveolin-1. Of note, caveolin-1 localization (fractions 2 to 3), which includes the predominant caveolin-containing fraction,3 was not changed after Ang II stimulation. This result was confirmed by coimmunoprecipitation assays showing that Rac1 and caveolin-1 were not bound in the basal state, and Ang II stimulation significantly increased Rac1 association with caveolin-1 with the peak at 5 minutes, which gradually decreased over 30 minutes (Figure 1B). Because microtubules are involved in caveolin-mediated trafficking and protein movement,16,22 we tested whether microtubules are involved in Ang II–stimulated Rac1 recruitment into caveolae. As shown in Figure 1A, fractionation experiments demonstrate that the microtubule depolymerizing drug nocodazole shifted the Ang II–induced mobilized Rac1 from caveolin to noncaveolin-containing membranes. Consistent with this result, the Ang II–induced increase in the amount of Rac1 that coprecipitated with caveolin-1 was diminished by nocodazole treatment (Figure 1C), confirming movement of Rac1 out of caveolae-like microdomains. Together, these data suggest that intact microtubules play an important role for Ang II–stimulated Rac1 movement into caveolae-like microdomains.
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Because we have shown previously that the AT1R moves into a caveolin-enriched fraction after Ang II stimulation,18 we next examined whether microtubules are involved in this response. Interestingly, nocodazole completely inhibited Ang II–stimulated AT1R movement into the caveolin-enriched fraction 3 (Figure 2A and 2B). In contrast, a large amount of EGF-Rs are found in caveolae/lipid rafts (fractions 2 to 4) in basal state, and Ang II stimulation significantly reduced the amount of EGF-R in these fractions (70±2% decrease from the basal, P<0.05; Figure 2A and B). Importantly, nocodazole had no effect on the Ang II–induced reduction of EGF-R localization in the caveolae/lipid raft fractions (72±1.1% decrease from the basal; P<0.05; Figure 2B). Thus, microtubules are required for AT1R trafficking into caveolae/lipid rafts but not for EGF-R exiting from these microdomains. Of note, tyrosine phosphorylated EGF-R, as measured by antiphospho-EGF-R antibody raised against autophosphorylation site (Tyr1068), was not found in caveolae/lipid rafts in either basally or in Ang II–stimulated cells (data not shown), which is consistent with our previous finding that transactivated EGF-Rs localize predominantly at focal adhesions.3
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To confirm the specificity of nocodazole on microtubules in VSMCs, we examined its effects on microtubule and the actin cytoskeleton structure (Figure I, available online at http://atvb.ahajournals.org). Microtubules stained with 
-tubulin were observed as filamentous networks coursing through the cytoplasm. Nocodazole (100 µmol/L) caused a complete disappearance of filamentous -tubulin staining without affecting the actin cytoskeleton stained with phalloidin, suggesting that nocodazole specifically disrupts microtubule structure. Stabilization of microtubules with taxol (30 µmol/L) renders them relatively resistant to nocodazole disruption.
Because nocodazole disrupts microtubules and inhibits Ang II–induced Rac1 movement into caveolin-enriched membrane fractions, we posited a role for microtubules in ROS-dependent Ang II signaling in VSMCs. As shown in Figure 3A, nocodazole significantly inhibited Ang II–induced H2O2 production, as determined by dichlorofluorescein diacetate (DCF-DA) fluorescence. Importantly, the basal fluorescence level was not significantly changed (P>0.05) after nocodazole treatment, eliminating the possibility that nocodazole nonspecifically interfered with the DCF-DA fluorescence signals.
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Because Rac1 is a critical component of NAD(P)H oxidase activation by Ang II in VSMC,7 we examined effects of nocodazole on Ang II–stimulated Rac1 activation, as measured by a pull-down assay that quantifies binding of activated, GTP-bound Rac to its effector p21-activated kinase (Figure 3B). The Ang II–stimulated increase in the Rac–GTP level was not decreased but was in fact enhanced slightly by nocodazole treatment under conditions in which ROS formation was not significantly increased (Figure 3A).
Because Rac GTP–loading and translocation from the cytosol to plasma membranes are critical steps for activation of NAD(P)H oxidase,8 we examined whether microtubule-dependent ROS formation was related to alterations in Rac1 translocation. As shown in Figure 3C, Ang II caused a rapid and significant increase in Rac1 in the membrane fraction that peaked at 2 minutes, which was significantly inhibited by nocodazole. Of note, nocodazole alone caused mislocalization of Rac1 to the membrane fraction in the basal state, which may be viewed in the context of Figure 1 showing the presence of Rac1 in noncaveolin-containing membrane fractions in microtubule-disrupted cells. Together, these results are consistent with the notion that intact microtubules are necessary for proper localization and targeting of Rac1 to the caveolin-enriched membrane fraction but not for GTP loading of Rac1. This spatial localizing mechanism may be important for the Ang II–induced increase in H2O2 production via activation of NAD(P)H oxidase in VSMCs.
Because we have demonstrated previously that caveolae/lipid rafts and ROS derived from NAD(P)H oxidase play an essential role in Ang II–induced EGF-R transactivation,3,4 we examined the role of microtubules in transmodulation of EGF-R by Ang II. As shown in Figure 4A, nocodazole and another microtubule-depolymerizing agent, colchicine, significantly inhibited Ang II–induced tyrosine phosphorylation of EGF-R. In contrast, stabilization of microtubules with taxol (30 µmol/L) had no effect on Ang II–mediated EGF-R transmodulation but prevented the inhibitory effect of nocodazole (data not shown). These data indicate that an intact microtubule network is required for Ang II–mediated transmodulation of EGF-Rs in VSMCs.
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Because microtubules are involved in coupling of the AT1Rs to the NAD(P)H oxidase (Figure 3), we tested whether they are required for ROS-induced or EGF-induced phosphorylation of EGF-R. As shown in Figure 4B, disruption of microtubules with nocodazole had no effect on the ability of exogenously applied H2O2 or EGF to induce phosphorylation of EGF-R. These results suggest that microtubules are not required for ROS-mediated or EGF-mediated EGF-R activation and provide evidence that nocodazole does not affect intrinsic tyrosine kinase activity of EGF-R.
To gain further insights into functional consequences of disruption of microtubules in Ang II signaling, we examined effects of nocodazole on phosphorylation of ROS-dependent kinases Akt and ROS-independent kinases extracellular signal-regulated kinase (ERK) 1/2, both of which are involved in Ang II–induced VSMC hypertrophy.23 As shown in Figure 5A, disruption of microtubules with nocodazole significantly inhibited Ang II–induced Akt phosphorylation, whereas ERK1/2 phosphorylation was not affected. Moreover, to test the possibility that microtubule disruption interferes selectively with caveolae/lipid rafts–mediated signaling events, we determined effects of plasma membrane cholesterol depletion with ß-cyclodextrin, which inhibits EGF-R transactivation by Ang II,3 on phosphorylation of Akt and ERK1/2. ß-Cyclodextrin almost completely abolished Ang II–induced phosphorylation of Akt without affecting ERK1/2 phosphorylation. These results are consistent with the notion that ROS-dependent as well as caveolae/lipid raft–dependent AT1R signaling events are dependent on intact microtubule structure in VSMCs.
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Finally, to assess the role of microtubules in hypertrophy, we examined the effect of nocodazole on Ang II–stimulated [3H]leucine incorporation. As shown in Figure 5B, nocodazole partially but significantly inhibited the Ang II–induced response. Inhibitory effects of nocodazole are not caused by toxic effects because the trypan blue exclusion test for cell viability indicated that cells treated with nocodazole were >98% viable. These results indicate that an intact microtubule network is required for Ang II–induced hypertrophy, at least in part through regulating ROS-dependent signaling pathways.
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Discussion |
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Microtubules play an important role in membrane trafficking and temporal–spatial organization of signal transduction. Ang II–stimulated signaling in VSMCs is dependent on ROS derived from NAD(P)H oxidase and targeting of relevant molecules to caveolin-containing membranes.3,4 Translocation of Rac1 to the plasma membrane is an essential step for activation of NAD(P)H oxidase.8,9,24 We examined the role of microtubules in spatial targeting of Rac1 and AT1R, as well as in ROS-dependent Ang II signaling in VSMCs. Here we show that Ang II promotes Rac1 translocation into caveolae/lipid rafts and its association with caveolin-1 through mechanisms that are dependent on intact microtubules. We also found that microtubules are involved in Ang II–stimulated AT1R trafficking into caveolae-like microdomains, ROS production, ROS-dependent EGF-R transactivation, and Akt phosphorylation as well as vascular hypertrophy.
Compartmentalization of signaling molecules in specialized membrane microdomains is required for selective and efficient activation of downstream signaling events. Here we demonstrate that Rac1 is found in both cytosol and noncaveolae heavy-density membrane fractions in basal state and that Ang II stimulation promotes recruitment of Rac1 to light-density membrane fractions containing caveolin-1 (Figures 1 and 3
). Coimmunoprecipitation experiments confirmed the physical association between Rac1 and caveolin-1 after Ang II stimulation (Figure 1), which is consistent with the fact that Rac1 contains a "caveolin-binding motif."13 Previous reports show that Rac1 is localized basally in caveolae in cardiomyocytes20 and Rat-1B cells.19 Platelet-derived growth factor stimulates recruitment of additional Rac1 to caveolae in cardiomyocytes,20 whereas stretch induces dissociation of Rac1 from caveolae in Rat-1B cells.19 Importantly, Rac1 association with and dissociation from caveolae are essential for agonist-induced activation of downstream signaling.19,20 We have shown previously that Ang II stimulation rapidly promotes AT1R movement into a caveolin-enriched fraction and its association with caveolin-1 in VSMCs.17 As noted, the Nox1 NAD(P)H oxidase subunit is found in caveolin-enriched fractions.18 We also reported that EGF-R initially binds caveolin, but this association is disrupted by Ang II stimulation, which is an essential step in transactivation of EGF-R in VSMCs.3 Thus, Ang II–stimulated recruitment of Rac1 into caveolae/lipid rafts and association with caveolin may be required for activation of Nox-based NAD(P)H oxidase and downstream ROS-dependent signaling events such as EGF-R transactivation.4
Because microtubules play an important role in caveolae-mediated trafficking and protein movement,1,16 we tested whether microtubules are involved in Ang II–stimulated Rac1 trafficking into caveolae/lipid rafts. We found that disruption of microtubules with nocodazole inhibits Rac1 translocation from cytosol and noncaveolae membrane fractions into caveolin-enriched membrane fractions. Interestingly, nocodazole alone caused mislocalization of Rac1 to the plasma membrane and a slight increase in Rac1 activity in basal state (Figure 3). Although the underlying mechanism remains unknown, it is possible that this is caused by activation of microtubule-associated Rac–guanine nucleotide exchange factor (GEF) induced by microtubule depolymerization.25 We confirmed that nocodazole specifically disrupts microtubules without affecting the structure of the actin cytoskeleton, which is minimally perturbed in the presence of the microtubule stabilizing agent taxol (Figure I). Our results suggest that intact microtubules play an important role in the proper positioning of Rac1 and Ang II–stimulated trafficking of Rac1 to caveolin-enriched fractions in VSMCs. Consistent with our results, Putnam et al10 reported that microtubules are involved in mechanical stress-stimulated Rac1 translocation to the plasma membrane in VSMCs. Similar to the findings with Rac1, there are several reports suggesting that glucose transporter 4 (GLUT4) translocation to the plasma membrane induced by insulin in adipocytes is also dependent on intact microtubules.26,27
The mechanism by which intact microtubules are involved in Rac1 trafficking into the caveolae-like microdomains is unclear. Fukata et al28 reported that Rac1 associates indirectly with the microtubule tip-binding protein cytoplasmic linker protein-170 and recruits microtubules to the leading edge of motile cells, thereby localizing Rac1 at this site. It has also been shown that activated Rac1 is recruited to the tip of microtubules through binding to the GEF–H1, a Rac–GEF.29 Hotta et al30 reported that Rac1 interacts directly with kinectin, a membrane-anchoring protein of kinesin that is a motor transporting vesicular cargo, which is required for Rac1 moving along microtubules. Moreover, GLUT4 trafficking along microtubules has been shown to be mediated through conventional kinesin KIF5B in adipocytes.27 Whether similar mechanisms are involved in Ang II–stimulated Rac1 movement into caveolin-enriched fractions in VSMCs requires further investigation.
The present study also demonstrates that disruption of microtubules significantly inhibits Ang II–stimulated AT1R trafficking into caveolae/lipid rafts, H2O2 production, its downstream ROS-dependent EGF-R phosphorylation, and Akt activation. Importantly, nocodazole has no effect on Ang II–stimulated EGF-R exiting from caveolin-enriched fractions (Figure 2) nor H2O2-induced or EGF-induced phosphorylation of EGF-R (Figure 4). Moreover, transactivated EGF-Rs are not present in caveolae/lipid rafts. We showed originally that AT1R-mediated signaling in VSMC is biphasic and that internalization of the agonist/receptor complex into a "signaling domain" is required for the tonic phase of signaling but not for initial phospholipase C activation.31 We also demonstrated that Ang II stimulates AT1R movement into caveolin-enriched fractions, which are required for Ang II–induced transactivation of EGF-R but not for initial activation of Ca2+ and cSrc.3 Importantly, Seshiah et al7 reported that Ang II–stimulated NAD(P)H oxidase activation is biphasic, and Rac1 pathway is involved in the second phase of oxidase activation, which serves as a feed-forward mechanism of activation of signaling pathways, such as EGF-R transactivation and Rac1, to amplify NAD(P)H oxidase activity. They also showed that rapid, initial ROS production at 30 sec is mediated through protein kinase C, which is activated by phospholipase C–derived diacylglycerol, suggesting that the initial phase of ROS production may occur in noncaveolin lipid rafts. Thus, our findings are consistent with the possibility that microtubule-dependent AT1R and Rac1 trafficking into caveolae/lipid rafts where Nox1 localizes18 is required for the second phase of NAD(P)H oxidase activation, thereby promoting ROS-dependent Ang II signaling such as EGF-R transactivation and its downstream Akt phosphorylation in VSMCs.
As noted, nocodazole has no effect on Ang II–stimulated EGF-R moving out of caveolae/lipid rafts (Figure 2), GTP–GDP exchange for Rac1 (Figure 3), or ERK1/2 phosphorylation (Figure 5). However, disruption of microtubule structure significantly inhibits vascular hypertrophy (Figure 5). We have shown previously that Ang II–induced hypertrophy is mediated through ROS-dependent and ROS-independent kinases such as Akt and ERK1/2, respectively.23,32 Furthermore, cholesterol depletion by ß-cyclodextrin dramatically inhibits EGF-R transactivation4 and phosphorylation of Akt without affecting ERK1/2 phosphorylation (Figure 5). Together, these results suggest that an intact microtubule system plays an important role for specific activation of ROS-dependent as well as caveolae/lipid raft-dependent AT1R signaling pathways that are linked to vascular hypertrophy.
In summary, the present study suggests that intact microtubules are required for proper AT1R and Rac1 trafficking into caveolae-like membrane microdomains, which is essential for activation of growth-related ROS-dependent signaling. These findings may provide insight into an essential role of microtubules for spatial–temporal organization of ROS-dependent as well as caveolae/lipid rafts–dependent AT1R signaling linked to vascular hypertrophy.
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Acknowledgments |
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Acknowledgments
This work was supported by National Institutes of Health grant HL60728 (R.W.A., M.U.-F.) and an American Heart Association national scientist development grant (to M.U.-F.). We would like to thank Dr Sonia-Athena P. Karabina for helping caveolae purification and Pam Daly and Linda Rice for editorial assistance.
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Footnotes |
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L.Z. and M.U.-F. contributed equally to this work.
Received April 16, 2004; accepted May 4, 2004.
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M. Ushio-Fukai and R. W. Alexander Caveolin-Dependent Angiotensin II Type 1 Receptor Signaling in Vascular Smooth Muscle Hypertension, November 1, 2006; 48(5): 797 - 803. [Full Text] [PDF]
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H. Ohtsu, H. Suzuki, H. Nakashima, S. Dhobale, G. D. Frank, E. D. Motley, and S. Eguchi Angiotensin II Signal Transduction Through Small GTP-Binding Proteins: Mechanism and Significance in Vascular Smooth Muscle Cells Hypertension, October 1, 2006; 48(4): 534 - 540. [Full Text] [PDF]
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 L. S. Terada Specificity in reactive oxidant signaling: think globally, act locally J. Cell Biol., August 28, 2006; 174(5): 615 - 623. [Abstract] [Full Text] [PDF]
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 M. Ushio-Fukai Localizing NADPH Oxidase-Derived ROS Sci. Signal., August 22, 2006; 2006(349): re8 - re8. [Abstract] [Full Text] [PDF]
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X. C. Li, O. A. Carretero, L. G. Navar, and J. L. Zhuo AT1 receptor-mediated accumulation of extracellular angiotensin II in proximal tubule cells: role of cytoskeleton microtubules and tyrosine phosphatases Am J Physiol Renal Physiol, August 1, 2006; 291(2): F375 - F383. [Abstract] [Full Text] [PDF]
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 R. E. Clempus and K. K. Griendling Reactive oxygen species signaling in vascular smooth muscle cells Cardiovasc Res, July 15, 2006; 71(2): 216 - 225. [Abstract] [Full Text] [PDF]
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 M. Hoshijima Mechanical stress-strain sensors embedded in cardiac cytoskeleton: Z disk, titin, and associated structures Am J Physiol Heart Circ Physiol, April 1, 2006; 290(4): H1313 - H1325. [Abstract] [Full Text] [PDF]
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 J. H. Brown, D. P. Del Re, and M. A. Sussman The Rac and Rho Hall of Fame: A Decade of Hypertrophic Signaling Hits Circ. Res., March 31, 2006; 98(6): 730 - 742. [Abstract] [Full Text] [PDF]
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 R.M. Touyz, G. Yao, M.T. Quinn, P.J. Pagano, and E.L. Schiffrin p47phox Associates With the Cytoskeleton Through Cortactin in Human Vascular Smooth Muscle Cells: Role in NAD(P)H Oxidase Regulation by Angiotensin II Arterioscler Thromb Vasc Biol, March 1, 2005; 25(3): 512 - 518. [Abstract] [Full Text] [PDF]
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