Therapeutic potential of RhoA/Rho kinase inhibitors in pulmonary hypertension.
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.
Oka
M
M
Department of Pharmacology and Center for Lung Biology, University of South Alabama, College of Medicine, Mobile, AL 36688, USA. moka@usouthal.edu
Fagan
K A
KA
Jones
P L
PL
McMurtry
I F
IF
D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047428:Protein Kinase Inhibitors; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein