© 2000 American Heart Association, Inc.
Editorial |
Targeting Rho in Cardiovascular Disease
From the Vascular Medicine Unit, Cardiovascular Division, Brigham & Women’s Hospital and Harvard Medical School (J.K.L.), Boston, Mass, and Medical Clinic III, University of Saarland (U.L), Homburg, Germany.
Correspondence to James K. Liao, Vascular Medicine Unit, 221 Longwood Ave, LMRC-322, Boston, MA 02115. E-mail jliao{at}rics.bwh.harvard.edu
Key Words: GTP-binding proteins • gene regulation • cytoskeleton • isoprenoids • cholesterol
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Introduction |
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 Top Introduction References |
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What began as molecular switches linking cell surface receptors to the reorganization of the actin cytoskeleton has now emerged as an important mediator of cardiovascular disease. The low-molecular-weight GTPases of the Rho family have appeared with increasing frequency in the cardiovascular literature. This interest stems from two seemingly opposite disciplines. From a basic science perspective, increasing evidence suggests a central role of Rho-dependent actin cytoskeleton in mediating changes in cell shape, contractility, and motility.1 However, how these actin cytoskeletal effects of Rho translate into cardiovascular pathophysiology is not entirely evident. From a clinical perspective, large prospective trials with 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors or statins suggest that these agents may have beneficial effects in cardiovascular disease in addition to their cholesterol-lowering effects.2 The realization that statins also inhibit isoprenoid synthesis,3 which is required for the posttranslational modification of Rho, has shifted the focus from a lipid-dependent effect of statins to their direct effects on Rho in the vasculature.
Several important pieces of the puzzle, which will bridge the biological functions of Rho with the clinical benefits of statins, are still missing. Foremost, what is the relationship between Rho and cardiovascular disease? In this issue of Circulation Research, Hernández-Perera et al4 provide additional evidence that Rho GTPases may play an important role in mediating vascular disease. They show that Rho is required for basal expression of preproendothelin-1 in vascular endothelial cells and that statins inhibit preproendothelin-1 expression by blocking Rho geranylgeranylation. The clinical relevance of these findings is underscored by the fact that preproendothelin-1 gives rise to endothelin-1, a potent vasoconstrictor and mitogen that regulates vascular tone and remodeling.5 Therefore, these findings fill in some of the missing pieces of the puzzle by linking the inhibition of Rho with the cholesterol-independent effects of statins. However, it is not known whether the actin cytoskeleton is involved in the regulation of preproendothelin-1 as it is in the case of endothelial nitric oxide synthase (eNOS)6 and tissue-type plasminogen activator.7 Interestingly, in contrast to eNOS, in which Rho regulates gene expression by altering mRNA stability,8 the effects of Rho on preproendothelin-1 seem to be transcriptional.
The Rho GTPases are members of the Ras superfamily of small
GTP-binding proteins.1 They consist of at least 14
distinct proteins ranging from 20 to 24 kDa, which can be additionally
subdivided into Rho, Rac, and Cdc42.1 Rho GTPases are
major substrates for posttranslational modification by isoprenylation,
and isoprenylation targets Rho GTPases to the membrane.1 9
Similar to the 
subunit of heterotrimeric G proteins, Rho proteins
cycle between the active GTP-bound and the inactive GDP-bound states.
Activators of Rho include growth factors,
cytokines, integrins, and G protein–coupled receptor ligands
or hormones such as bradykinin or lysophosphatidic
acid.1 9 A key step in the activation of Rho is the
attachment of geranylgeraniol, an isoprenoid intermediate of the
cholesterol biosynthesis pathway (see Figure
). This
posttranslational lipid modification is necessary for the translocation
of inactive Rho from the cytosol to the membrane. Therefore, statins
which block geranylgeraniol synthesis, or geranylgeranyl transferase
inhibitors which prevent the attachment of geranylgeraniol
to Rho, inhibit Rho membrane translocation and activity. Indeed,
evidence suggests that inhibition of Rho isoprenylation mediates many
of the cholesterol-independent effects of statins not only
in vascular wall cells8 10 but also in
leukocytes11 and bone.12
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Each member of the Rho family serves specific functions for cell shape, motility, secretion, and proliferation, although overlapping functions between the members could be observed in overexpressed systems. The activation of Rho in Swiss 3T3 fibroblasts by extracellular ligands, such as platelet-derived lysophosphatidic acid, leads to myosin light chain phosphorylation and formation of focal adhesion complexes.1 9 Indeed, Rho-associated protein kinase increases the sensitivity of vascular smooth muscle to calcium in hypertension13 and coronary spasm.14 In contrast, activation of Rac leads to the formation of lamellipodia and membrane ruffles, whereas activation of Cdc42 induces actin-rich surface protrusions called filo-podia. These distinct but complementary functions of Rho family members also extend to their effects on cell signaling. When cells undergo reorganization of their actin cytoskeleton in response to extracellular signals such as growth factors or during cell movement and mitosis, they alter the three-dimensional colocalization of intracellular proteins.1 9 Thus, changes in Rho-induced actin cytoskeleton can affect intracellular transport, membrane trafficking, mRNA stability, and gene transcription. Therefore, it is not too surprising to find that the heart and vasculature respond to mechanical forces by changes in cell shape and gene expression. In this respect, Rho-induced changes in the actin cytoskeleton and gene expression are interrelated.
Clinical trials with statins have led to increased understanding
of the role of Rho in cardiovascular disease. For
example, in cardiac myocytes, RhoA and Rac1 have been shown to mediate
hypertrophy, myofibrillogenesis, and the reexpression of
fetal genes such as atrial natriuretic
factor.15 Therefore, it is interesting to speculate
whether some of the beneficial effects of statin treatment in
hypertension and heart failure may be attributable to inhibition of Rho
proteins in the heart. In vascular smooth muscle cells, Rho promotes
cell-cycle progression and proliferation, which are central events in
the pathogenesis of vascular lesions, including postangioplasty
restenosis, transplant arteriosclerosis,
and vein graft occlusion. The molecular mechanism is attributable, in
part, to Rho-induced posttranslational destabilization of the
cyclin-dependent kinase inhibitor
p27kip1.16 Indeed, statins, which
effectively decrease the incidence of transplant-associated
arteriopathy,17 attenuate smooth muscle cell proliferation
through inhibition of RhoA geranylgeranylation.10 Recent
studies also suggest that statins may exert additional antiinflammatory
and antioxidant effects on the vascular wall. In certain cell types,
Rho mediates the activation of the proinflammatory transcription factor
nuclear factor–
B in response to cytokines.18
Furthermore, Rho proteins may be involved in mediating increases in
oxidative stress. A major source of oxidants in vascular wall cells is
the NAD(P)H oxidase.19 The Rho family member Rac1 is a
regulatory component of the NAD(P)H oxidase in several cell types,
including neutrophils and vascular wall cells. Indeed, inhibition of
Rac1 isoprenylation by statins inhibits the release of reactive oxygen
species in endothelial cells.20 Finally,
Rho plays an important role in regulating endothelial
function and gene expression, as illustrated in the present study
by Hernández-Perera et al.4 Besides upregulating
preproendothelin-1 expression, RhoA negatively regulates the
production of endothelium-derived nitric oxide
via Rho-induced changes in the endothelial actin
cytoskeleton.8 Indeed, direct inhibition of Rho by
Clostridium botulinum C3 transferase or disruption of the
endothelial actin cytoskeleton by cytochalasin D leads
to increases in aortic eNOS expression and activity in
mice.6
In summary, Rho seems to play an important role in cardiovascular disease, and inhibition of Rho may account for some of the cholesterol-independent pleiotropic effects of statins. However, additional studies are needed to understand exactly how Rho is activated, what its downstream targets are, and how it regulates cellular functions under pathophysiological conditions. Given the therapeutic implications of statin therapy, targeting Rho through inhibiting its geranylgeranylation or blocking its downstream effector Rho kinase may indeed yield some clinical benefits. However, it is too early to tell whether targeting Rho alone will produce favorable outcomes. The beneficial effects may be offset by the adverse effects of Rho inhibition, because Rho is critically involved in many important cellular functions. As the present study by Hernández-Perera et al4 reminds us, there is still much to be learned about how Rho is regulated and what it regulates.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
Dr James Liao has equity interests and is a scientific consultant for eNOS Pharmaceuticals, Inc.
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References |
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C. Berry, R. Touyz, A. F. Dominiczak, R. C. Webb, and D. G. Johns Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2337 - H2365. [Abstract] [Full Text] [PDF]
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P. Di Napoli, A. Antonio Taccardi, A. Grilli, R. Spina, M. Felaco, A. Barsotti, and R. De Caterina Simvastatin reduces reperfusion injury by modulating nitric oxide synthase expression: an ex vivo study in isolated working rat hearts Cardiovasc Res, August 1, 2001; 51(2): 283 - 293. [Abstract] [Full Text] [PDF]
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S. Chrissobolis and C. G. Sobey Evidence That Rho-Kinase Activity Contributes to Cerebral Vascular Tone In Vivo and Is Enhanced During Chronic Hypertension : Comparison With Protein Kinase C Circ. Res., April 27, 2001; 88(8): 774 - 779. [Abstract] [Full Text] [PDF]
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W. Ni, K. Egashira, C. Kataoka, S. Kitamoto, M. Koyanagi, S. Inoue, and A. Takeshita Antiinflammatory and Antiarteriosclerotic Actions of HMG-CoA Reductase Inhibitors in a Rat Model of Chronic Inhibition of Nitric Oxide Synthesis Circ. Res., August 31, 2001; 89(5): 415 - 421. [Abstract] [Full Text] [PDF]
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C. Urbich, E. Dernbach, A. M. Zeiher, and S. Dimmeler Double-Edged Role of Statins in Angiogenesis Signaling Circ. Res., April 5, 2002; 90(6): 737 - 744. [Abstract] [Full Text] [PDF]
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M. Eto, T. Kozai, F. Cosentino, H. Joch, and T. F. Luscher Statin Prevents Tissue Factor Expression in Human Endothelial Cells: Role of Rho/Rho-Kinase and Akt Pathways Circulation, April 16, 2002; 105(15): 1756 - 1759. [Abstract] [Full Text] [PDF]
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