Skip to main content

RhoA/Rho-Kinase as a Therapeutic Target in Asthma

Buy Article:

$63.00 plus tax (Refund Policy)


Rho-kinase is an effector molecule of RhoA, a monomeric GTP-binding protein, and causes Ca2+ sensitization via inactivation of myosin phosphatase. The major physiological functions of Rho-kinase include contraction, migration, and proliferation in cells. These actions are thought to be related to the pathophysiological features of asthma, i.e., airflow limitation, airway hyperresponsiveness, β-adrenergic desensitization, eosinophil recruitment and airway remodeling. Here, the roles of RhoA/Rho-kinase in the pathophysiology and treatment of asthma were investigated. In airway smooth muscle, pre-exposure to chemical mediators released from inflammatory cells markedly enhances methacholine-induced contraction without elevating intracellular concentrations of Ca2+. This augmented responsiveness to methacholine involves the phosphorylation of myosin phosphatase targeting protein 1 (MYPT1) via Rho-kinase, however, it is attenuated by pre-treatment with Rho-kinase inhibitors such as Y-27632 and HA-1077. Airway smooth muscle contraction due to asthma-related substances such as contractile agonists and reactive oxygen species is suppressed by these Rho-kinase inhibitors. Reduced responsiveness to β-adrenergic receptor agonists occurs via Ca2+ sensitization, after exposure to lysophospholipids and proteases released from inflammatory cells. This β-adrenergic desensitization is also attenuated in the presence of Y-27632. Furthermore, the proliferation of airway smooth muscle cells is elevated by Rho-kinase, however, it is markedly suppressed by Y-27632. Antigen challenges cause hyperresponsiveness and eosinophilia in the airways; however, these reactions are markedly suppressed by these Rho-kinase inhibitors. These findings indicate that RhoA/Rhokinase is involved in the pathophysiology of asthma, and suggest that Rho-kinase inhibitors have therapeutic potential for prohibiting these features. In conclusion, RhoA/Rho-kinase is a novel target molecule for the treatment of asthma.

Keywords: Airway smooth muscle; Ca2+ sensitization; a small G protein; airway hyperresponsiveness; airway remodeling; bronchial asthma; eosinophil; β2-adrenergic desensitization

Document Type: Research Article


Affiliations: Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumaicho, Showa-ku, Nagoya 466-8550, Japan.

Publication date: November 1, 2008

More about this publication?
  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.

Access Key

Free Content
Free content
New Content
New content
Open Access Content
Open access content
Subscribed Content
Subscribed content
Free Trial Content
Free trial content
Cookie Policy
Cookie Policy
Ingenta Connect website makes use of cookies so as to keep track of data that you have filled in. I am Happy with this Find out more