The role of RhoA-mediated Ca2+ sensitization of bronchial smooth muscle contraction in airway hyperresponsiveness
The role of RhoA-mediated Ca2+ sensitization of bronchial smooth muscle contraction in airway hyperresponsiveness
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DOI：
10.1540/jsmr.40.155
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发表时间：
2004-10-01
影响因子：
--
通讯作者：
Misawa, Miwa
中科院分区：
文献类型：
--
作者：
Chiba, Yoshihiko;Misawa, Miwa
平滑肌收缩是通过钙离子依赖和非钙离子非依赖性途径介导的。后者被称为钙敏化，主要受单体GTP结合蛋白RhoA及其下游靶标Rho-Kinase的调控。最近的研究表明，在几种人类疾病中，增强的RhoA/Rho-Kinase信号可能参与了平滑肌收缩的升高。哮喘患者的特点之一是气道高反应性，其主要原因可能是支气管平滑肌收缩功能增强，也有报道称哮喘患者存在这种现象。在此，我们将讨论RhoA/Rho-Kinase介导的钙敏化的支气管平滑肌收缩在气道高反应性发病机制中的作用。激动剂诱导的Ca~(2+)敏化也是支气管平滑肌固有的。由于Ca~(2+)对RhoA失活剂、C3外切酶和Rho-Kinase抑制剂Y-27632敏感，因此RhoA/Rho-Kinase通路参与了这一信号转导过程。值得注意的是，在实验性哮喘中，RhoA/Rho-Kinase介导的支气管平滑肌收缩的钙敏化作用明显增强。此外，Y-27632还能解除收缩激动剂和抗原在体内引起的支气管痉挛。Y-27632还具有抑制抗原攻击诱导的气道高反应性的能力。因此，RhoA/Rho-Kinase通路可能成为开发哮喘新疗法的潜在靶点，尤其是在呼吸道高反应性方面。
Smooth muscle contraction is mediated by Ca2+-dependent and Ca2+-independent pathways. The latter Ca2+-independent pathway, termed Ca2+ sensitization, is mainly regulated by a monomeric GTP binding protein RhoA and its downstream target Rho-kinase. Recent studies suggest a possible involvement of augmented RhoA/Rho-kinase signaling in the elevated smooth muscle contraction in several human diseases. An increased bronchial smooth muscle contractility, which might be a major cause of the airway hyperresponsiveness that is a characteristic feature of asthmatics, has also been reported in bronchial asthma. Here, we will discuss the role of RhOA/Rho-kinase-mediated Ca2+ sensitization of bronchial smooth muscle contraction in the pathogenesis of airway hyperresponsiveness. Agonist-induced Ca2+ sensitization is also inherent in bronchial smooth muscle. Since the Ca2+ sensitization is sensitive to a RhoA inactivator, C3 exoenzyme, and a Rho-kinase inhibitor, Y-27632, the RboA/Rho-kinase pathway is involved in the signaling. It is of interest that the RhoA/Rho-kinase-mediated Ca2+ sensitization of bronchial smooth muscle contraction is markedly augmented in experimental asthma. Moreover, Y-27632 relaxes the bronchospasm induced by contractile agonists and antigens in vivo. Y-27632 also has an ability to inhibit airway hyperresponsiveness induced by antigen challenge. Thus, the RhoA/Rho-kinase pathway might be a potential target for the development of new treatments for asthma, especially in airway hyperresponsiveness.