Pulmonary arterial hypertension (PAH) is a disease with poor prognosis characterized by progressive elevation of pulmonary arterial pressure and vascular resistance due to pulmonary artery hyperconstriction and remodeling. However, the precise mechanism of PAH still remains to be elucidated. Although
anticoagulant agents,
vasodilators (e.g.,
prostaglandins,
sildenafil, and
bosentan), and
lung transplantation are currently used for the treatment of PAH, more effective treatment needs to be developed.
Rho-kinase causes vascular smooth muscle hyperconstriction and
vascular remodeling through inhibition of
myosin phosphatase and activation of its downstream effectors. In a series of experimental and clinical studies, we have demonstrated that
Rho-kinase-mediated pathway plays an important role in various cellular functions, not only in vascular smooth muscle hyperconstriction but also in actin cytoskeleton organization, cell adhesion and motility, cytokinesis, and gene expression, all of which may be involved in the pathogenesis of
arteriosclerosis. We also have recently demonstrated that
Rho-kinase is activated in animal models of PAH with different etiologies (
monocrotaline and chronic
hypoxia) associated with enhanced pulmonary vasoconstricting and proliferating responses, impaired endothelial
vasodilator functions, and pulmonary remodeling. Indeed, we were able to demonstrate that intravenous
fasudil, a selective
Rho-kinase inhibitor, exerts acute pulmonary
vasodilator effects in patients with severe PAH who were refractory to conventional
therapies. Taken together, our findings indicate that
Rho-kinase is a novel and important therapeutic target of PAH in humans and that
Rho-kinase inhibitors are a promising new class of drugs for the fatal disorder.