Pulmonary arterial hypertension (PAH) is a fatal 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, pulmonary
vasodilators, 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, it has been 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 expressions, all of which may be involved in the pathogenesis of
arteriosclerosis.
Rho-kinase is activated in animal models of PAH (
monocrotaline and chronic
hypoxia) associated with enhanced pulmonary vasoconstriction and proliferation, impaired endothelial
vasodilator functions, and pulmonary remodeling. Therapeutic application of
Rho-kinase inhibitors reverses established experimental
pulmonary hypertension. Further, administration or inhalation of
Rho-kinase inhibitors exerts acute pulmonary vasodilation in patients with PAH who were refractory to conventional
therapies. Taken together,
Rho-kinase is a novel and important therapeutic target of PAH, and
Rho-kinase inhibitors are a promising new class of drugs for this fatal disorder.