title: Role of Rho-kinase and its inhibitors in pulmonary hypertension.
abstract: Pulmonary hypertension (PH) is an incurable disease with a dreadful survival rate. The disease is characterized by sustained vasoconstriction, progressive vascular remodeling, and irreversible right heart dysfunction. While hypoxic pulmonary vasoconstriction (HPV) is known to be the main pathophysiological factor causing the rise in pulmonary arterial pressure, biological mechanisms leading to HPV and vascular remodeling are multiple and complex and, as yet, incompletely understood. It is thought that molecular interactions and cross talks are involved in the pathogenesis of PH, perturbing the physiological balance between substances controlling vascular tone, cell growth and apoptosis. This balance is achieved by subtle interactions between factors acting as both vasodilators and inhibitors of cell growth like nitric oxide, prostacyclin, vasoactive intestinal peptide and molecules with potent vasoconstrictor and cell growth activities like endothelin-1. Recent in vivo studies showed that the Rho GTPase/RhoA pathway and its downstream effectors, the Rho-kinases (ROCK-1 and ROCK-2), had an important role in PH, due to its lasting effects on vasoconstriction and pulmonary cell proliferation leading to vascular remodeling. Beneficial effects obtained in vivo with Rho-kinase inhibitors (e.g.Y-27632 and fasudil) in experimental PH will hopefully lead to future clinical trials with new compounds selectively targeting this pathway, which is now proven to be detrimental when over-activated in both experimental animals and human patients.
authors.affiliation: Paris Descartes University, Medical School, Assistance Publique Hôpitaux de Paris, Service de Physiologie, Explorations Fonctionnelles Hôpital Cochin, 27 rue du faubourg Saint-Jacques, 75014 Paris, France.
authors.forename: Sy
authors.initials: S
authors.lastname: Duong-Quy
authors.forename: Yihua
authors.initials: Y
authors.lastname: Bei
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Liu
authors.forename: Anh Tuan
authors.initials: AT
authors.lastname: Dinh-Xuan
mesh_terms: D000818:Animals; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D047428:Protein Kinase Inhibitors; D054460:rho-Associated Kinases