ReviewRho and vascular disease
Introduction
The Rho family GTPases (of which Rho, Rac, Cdc42 are best characterised) are regulatory molecules that link surface receptors to organisation of the actin cytoskeleton [1] and regulate fundamental cellular processes [2], [3], [4], [5], [6]. In the vasculature, RhoA regulates smooth muscle contraction [7] and expression of smooth muscle differentiation marker genes [8] and has been implicated for a role in smooth muscle cell (SMC) phenotypic modulation [9], [10]. Both Rac and Rho are implicated in endothelial barrier function, endothelial migration and wound repair [11]. These observations, along with demonstrations that some of the beneficial effects of the statins may be due to their ability to inhibit Rho family GTPases [12] have led our laboratory and others to propose that members of the Rho family are critical to vascular function.
This review will examine the known roles of Rho family proteins in the vasculature, with particular emphasis on the role of RhoA and its impact on atherogenesis.
Section snippets
The Rho family of small GTPases
The gene for Rho (from ‘Ras homologous’) was first described in 1985 [13] as a cloning artefact from a gene family derived from the mollusc Aplysia gene library, and has since been found in almost all cells [14]. The Rho GTPases form a sub-group within the Ras superfamily of small GTP-binding proteins. To date, 22 Rho genes encoding more than 25 proteins have been identified in humans, and these have been divided into six groups [15] of which RhoA, Rac and Cdc42 are considered the ‘classical’
Inhibitors of Rho activity
Many of the functions of Rho family proteins have been elucidated using a range of inhibitors, the most prominent of these being the statins. Statins inhibit HMG CoA reductase, the rate-limiting enzyme of the mevalonate pathway through which cells synthesise cholesterol from acetate moieties (Fig. 2). However, by inhibiting mevalonate synthesis, statins also prevent the synthesis of isoprenoid intermediates, farnesylpyrophosphate and geranylgeranylpyrophosphate [70], lipid attachments important
Rho proteins in the vasculature
Rho family GTPases have been implicated for roles in almost every aspect of vascular biology, influencing the biology of endothelial cells, smooth muscle cells, leukocytes and platelets, and regulating such diverse processes as vasoreactivity and hypertension, inflammation and wound healing, neointimal formation and thrombosis. This review will focus on the role of Rho family proteins in the pathogenesis of atherosclerosis.
Concluding remarks
Rho family signalling pathways are intimately involved with regulation of the vasculature, influencing almost every aspect of vascular homeostasis and mediating the changes associated with atherogenesis. Rho proteins have been demonstrated to play a role in regulating endothelial barrier function, inflammation and transendothelial leukocyte migration, platelet activation, thrombosis and oxidative stress as well as smooth muscle contraction, migration, proliferation, differentiation and
Acknowledgements
This research was funded by the Heart Foundation of Australia and the Ronald Geoffrey Arnott Foundation.
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