Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: Bench to bedside research.
Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: Bench to bedside research.
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DOI：
10.1016/j.exer.2016.08.023
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发表时间：
2017-05
影响因子：
3.4
通讯作者：
Kopczynski C
中科院分区：
文献类型：
--
作者：
Rao PV;Pattabiraman PP;Kopczynski C
青光眼是全球不可逆转失明的主要原因。眼压升高被认为是原发性开角型青光眼的主要危险因素，青光眼是最常见的青光眼形式。虽然眼压升高的病因机制尚不完全清楚，但通过常规或小梁途径的房水(AH)排出障碍被认为是青光眼患者的主要原因。重要的是，降低眼压已经被证明可以减少视力丧失的进展，并且是所有类型青光眼的主要治疗方法。然而，目前可用于降低眼压的治疗选择有限，特别是当它与通过小梁通路促进AH流出有关时。为了应对这一挑战，在过去15年中进行的长凳和床边研究已经确定了抑制Rho激酶对降低眼压的重要性。Rho激酶是Rho GTPase信号的下游效应者，调节多种细胞类型的肌动蛋白动态。几个实验室的研究表明，抑制Rho激酶可通过松弛小梁网络来降低眼压，从而增加AH的流出。相反，小梁流出通路中Rho GTPase/Rho激酶信号的激活通过改变小梁网和Schlemm管组织的收缩、细胞黏附和通透性屏障特性，并通过影响细胞外基质的产生和纤维化活动来增加眼压。这篇文章是为了纪念已故的大卫·爱泼斯坦医学博士而写的，总结了基础和临床研究的结果，这些研究有助于认识Rho/Rho激酶信号通路在调节AH流出中的重要性，并有助于开发Rho激酶抑制剂作为青光眼治疗的有前途的降眼压药物。
Glaucoma is a leading cause of irreversible blindness worldwide. Elevated intraocular pressure (IOP) is considered to be a predominant risk factor for primary open angle glaucoma, the most prevalent form of glaucoma. Although the etiological mechanisms responsible for increased IOP are not completely clear, impairment in aqueous humor (AH) drainage through the conventional or trabecular pathway is recognized to be a primary cause in glaucoma patients. Importantly, lowering of IOP has been demonstrated to reduce progression of vision loss and is a mainstay of treatment for all types of glaucoma. Currently however, there are limited therapeutic options available for lowering IOP especially as it relates to enhancement of AH outflow through the trabecular pathway. Towards addressing this challenge, bench and bedside research conducted over the course of the last decade and a half has identified the significance of inhibiting Rho kinase for lowering IOP. Rho kinase is a downstream effector of Rho GTPase signaling that regulates actomyosin dynamics in numerous cell types. Studies from several laboratories have demonstrated that inhibition of Rho kinase lowers IOP via relaxation of the trabecular meshwork which enhances AH outflow. By contrast, activation of Rho GTPase/Rho kinase signaling in the trabecular outflow pathway increases IOP by altering the contractile, cell adhesive and permeability barrier characteristics of the trabecular meshwork and Schlemm’s canal tissues, and by influencing extracellular matrix production and fibrotic activity. This article, written in honor of the late David Epstein, MD, summarizes findings from both basic and clinical studies that have been instrumental for recognition of the importance of the Rho/Rho kinase signaling pathway in regulation of AH outflow, and in the development of Rho kinase inhibitors as promising IOP- lowering agents for glaucoma treatment.