Recent progress in the treatment of pulmonary arterial hypertension: Expectation for Rho-Kinase inhibitors

Yoshihiro Fukumoto, Shunsuke Tawara, Hiroaki Shimokawa

Research output: Contribution to journalReview article

58 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)309-320
Number of pages12
JournalTohoku Journal of Experimental Medicine
Volume211
Issue number4
DOIs
Publication statusPublished - 2007 Apr 5

Keywords

  • Pulmonary arterial hyperconstriction
  • Pulmonary arterial hypertension
  • Pulmonary arteriosclerosis
  • Rho-kinase

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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