Skip to main content

RhoA/Rho-Kinase as a Therapeutic Target in Asthma

Buy Article:

$63.00 plus tax (Refund Policy)

Abstract:

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

DOI: http://dx.doi.org/10.2174/092986708786242831

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.
ben/cmc/2008/00000015/00000027/art00007
dcterms_title,dcterms_description,pub_keyword
6
5
20
40
5

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
X
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