Therapeutic potential of RhoA/Rho kinase inhibitors in pulmonary hypertension

Abstract

A burgeoning body of evidence suggests that RhoA/Rho kinase (ROCK) signalling plays an important role in the pathogenesis of various experimental models of pulmonary hypertension (PH), including chronic hypoxia-, monocrotaline-, bleomycin-, shunt- and vascular endothelial growth factor receptor inhibition plus chronic hypoxia-induced PH. ROCK has been incriminated in pathophysiologic events ranging from mediation of sustained abnormal vasoconstriction to promotion of vascular inflammation and remodelling. In addition, the 3-hydroxy-3-methylglutaryl CoA reductase inhibitors, statins, which inhibit activation of RhoA by preventing post-translational isoprenylation of the protein and its translocation to the plasma membrane ameliorate PH in several different rat models, and may also be effective in PH patients. Also, phosphorylation of RhoA and prevention of its translocation to the plasma membrane are involved in the protective effect of the type 5-PDE inhibitor, sildenafil, against hypoxia- and bleomycin-induced PH. Collectively, these and other observations indicate that independent of the cause of PH, activation of the RhoA/ROCK pathway serves as a point of convergence of various signalling cascades in the pathogenesis of the disease. We propose that ROCK inhibitors and other drugs that inhibit this pathway might be useful in the treatment of various forms of PH.

Figure 1

Regulation of smooth muscle cell contraction. Vascular smooth muscle contraction is determined primarily by the balance in activities of Ca²⁺/calmodulin-dependent myosin light chain kinase (MLCK, contraction) and Ca²⁺-independent MLC phosphatase (MLCP, relaxation). G-protein-coupled receptor (GPCR) agonists (ET-1, endothelin-1; 5-HT, serotonin; TXA₂, thromboxane A₂; and so on) not only activate MLCK, but also inactivate MLCP by activation of RhoA/Rho kinase pathway and/or activation of the MLCP-inhibitor protein CPI-17 (not shown) to cause smooth muscle cell contraction. In some instances, Rho kinase activation can also induce Ca²⁺ signalling, and Ca²⁺ signals can activate RhoA/Rho kinase. IP₃, inositol 1,4,5-triphosphate; PLC; MYPT1, regulatory myosin-binding subunit of MLCP (modified from Nagaoka et al. (2005) Am J Respir Crit Care Med 171: 494–499).

Figure 2

Schematic illustration of possible pathways and effects of RhoA/Rho kinase signalling in the pathogenesis of pulmonary hypertension (PH) (modified from Fukumoto et al. (2007) Tohoku J Exp Med 211: 309–320).