© 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@rics.bwh.harvard.edu
Key Words: GTP-binding proteins • gene regulation • cytoskeleton • isoprenoids • cholesterol
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Introduction |
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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
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