Rho-kinase inhibition: a novel therapeutic target for the treatment of cardiovascular diseases

Abstract

The Rho/rho-kinase (ROCK) pathway has an important role in the pathogenesis of several cardiovascular diseases. The activation of ROCK is involved in the regulation of vascular tone, endothelial dysfunction, inflammation and remodeling. The inhibition of ROCK has a beneficial effect in a variety of cardiovascular disorders. Evidence from animal models and from clinical use of ROCK inhibitors, such as Y-27632, fasudil and statins (i.e. pleiotropic effects), supports the hypothesis that ROCK is a potential therapeutic target. This review provides a current understanding of the role of ROCK pathway in the regulation of vascular function and the use of ROCK inhibitors in the treatment of cardiovascular disorders.

FIGURE 1

The Rho GDP–Rho GTP signaling pathway from membrane to the cytosol. With the binding of Rho GDI to Rho-GDP, inactivated Rho-GDP is extracted from the membrane to the cytosol. When cells are stimulated with certain agonists, Rho-GDP is converted to Rho-GTP through the action of Rho GEF. Rho-GTP is then targeted to the specific targets. Rho GAP inactivates Rho by dephosphorylating GTP to GDP. The downstream effector of Rho is ROCK. Stimulation of GPCR also leads to ROCK activation via Rho GEF. Activated ROCK, mediated through, phosphorylates various downstream targets including the MBS of MLCP. Phosphorylation of MBS inhibits MLCP activity leading to increased MLC phosphorylation and actomyosin activation. Abbreviations: CaM, calcium/calmodulin; GPCR, G-protein-coupled receptor; MBS, myosin-binding subunit; MLCK, myosin light chain kinase; MLCP, myosin light chain phosphatase; Rho GAP, Rho GTPase-activating protein; Rho GDI, Rho guanine dissociation inhibitor; Rho GEF, Rho guanine nucleotide exchange factor; ROCK, Rho kinase. Stimulation is denoted by +; inhibition is denoted by –.

FIGURE 2

Current studies of ROCK inhibitors. ROCK inhibitors seem to be useful for treating disorders caused by arteriosclerotic diseases, vascular smooth muscle cell (VSMC) hypercontraction, other smooth muscle cell (SMC) disorders (e.g. bronchial asthma and glaucoma) and other diseases. The clinical usefulness of ROCK inhibitors remains to be fully elucidated. See Refs. [–119] in the reference list for the reference citations in the figure.