The role of the actomyosin system in regulating trabecular fluid outflow

Tian, Baohe; Gabelt, B’Ann T.; Geiger, Benjamin; Kaufman, Paul L.

doi:10.1016/j.exer.2008.08.008

Cited by 110 publications

(108 citation statements)

References 36 publications

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“…Regulation of mechanical and contractile properties of the pressure-sensitive TM cells is recognized to play a significant role in modulation of aqueous humor outflow and ocular pressure homeostasis (22,29,41,58,60). Although there is a substantial amount of phenomenological data in the literature regarding the possible role of the ECM and cytoskeletal integrity in modulation of aqueous humor outflow, the mechanistic understanding for these interactions has lagged behind (24,41,49,51). Thus identifying the molecular basis by which the ECM, cytoskeletal integrity, cellular tension, and mechanostransduction modulate outflow facility through the TM is vitally important for understanding of homeostasis of intraocular pressure.…”

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confidence: 99%

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confidence: 99%

“…Supportive evidence for this link comes from perfusion studies that used cytoskeletal modulating agents, such as actin depolymerizing agents, inhibitors of myosin light-chain kinase, myosin II, protein kinase C, Rho GTPase, and Rho kinase and from both in vitro and in vivo model systems (11,19,41,51). These studies suggest that agents that increase actin depolymerization and decrease cell-ECM interactions and myosin II phosphorylation within cells of the trabecular pathway increase aqueous humor outflow presumably by causing cellular relaxation and by altering the geometry and stiffness of the outflow pathway tissues and fluid flow through the inner wall of SC (41,51). Conversely, agents that activate Rho GTPase and myosin II activity, including lysophosphatidic acid (LPA), sphingosine-1-phosphate, TGF-␤ 2 , and endothelin-1, decrease aqueous humor outflow facility concomitant with increased contractile activity of the TM cells, indicating a potential importance of actomyosin organization and the contractile force generated by the actomyosin system in the regulation of aqueous humor drainage (16,33,39,57,63).…”

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confidence: 99%

“…Alterations in cytoskeletal isometric tension generated through actomyosin contraction in turn activates signaling pathways, which transduce intracellular events into outputs that determine how the cell interacts with its environment, as exemplified by cell-ECM adhesive interactions and ECM assembly and rigidity (4,20,42,53,65). TM cells exhibit smooth muscle-like physiology based on their electromechanical properties (58) and the expression profile of various smooth muscle-specific proteins, including ␣-smooth muscle actin (␣-SMA) and CPI-17 (11,39,51,58). Regulation of mechanical and contractile properties of the pressure-sensitive TM cells is recognized to play a significant role in modulation of aqueous humor outflow and ocular pressure homeostasis (22,29,41,58,60).…”

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Mechanistic basis of Rho GTPase-induced extracellular matrix synthesis in trabecular meshwork cells

Pattabiraman¹,

Rao

2010

American Journal of Physiology-Cell Physiology

174

222

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Pattabiraman PP, Rao PV. Mechanistic basis of Rho GTPaseinduced extracellular matrix synthesis in trabecular meshwork cells. Am J Physiol Cell Physiol 298: C749 -C763, 2010. First published November 25, 2009 doi:10.1152/ajpcell.00317.2009.-Elevated intraocular pressure arising from impaired aqueous humor drainage through the trabecular pathway is a major risk factor for glaucoma. To understand the molecular basis for Rho GTPase-mediated resistance to aqueous humor drainage, we investigated the possible interrelationship between actomyosin contractile properties and extracellular matrix (ECM) synthesis in human trabecular meshwork (TM) cells expressing a constitutively active form of RhoA (RhoAV14). TM cells expressing RhoAV14 exhibited significant increases in fibronectin, tenascin C, laminin, ␣-smooth muscle actin (␣-SMA) levels, and matrix assembly in association with increased actin stress fibers and myosin light-chain phosphorylation. RhoAV14-induced changes in ECM synthesis and actin cytoskeletal reorganization were mimicked by lysophosphatidic acid and TGF-␤2, known to increase resistance to aqueous humor outflow and activate Rho/Rho kinase signaling. RhoAV14, lysophosphatidic acid, and TGF-␤ 2 stimulated significant increases in Erk1/2 phosphorylation, paralleled by profound increases in fibronectin, serum response factor (SRF), and ␣-SMA expression. Treatment of RhoA-activated TM cells with inhibitors of Rho kinase or Erk, on the other hand, decreased fibronectin and ␣-SMA levels. Although suppression of SRF expression (both endogenous and RhoA, TGF-␤ 2-stimulated) via the use of short hairpin RNA decreased ␣-SMA levels, fibronectin was unaffected. Conversely, fibronectin induced ␣-SMA expression in an SRF-dependent manner. Collectively, data on RhoA-induced changes in actomyosin contractile activity, ECM synthesis/assembly, and Erk activation, along with fibronectin-induced ␣-SMA expression in TM cells, reveal a potential molecular interplay between actomyosin cytoskeletal tension and ECM synthesis/assembly. This interaction could be significant for the homeostasis of aqueous humor drainage through the pressure-sensitive trabecular pathway. fibronectin; actomyosin; extracellular signal-regulated kinases; serum response factor GLAUCOMA IS A SECOND MAJOR cause of blindness in the United States. A major risk factor for primary open-angle glaucoma is elevated intraocular pressure caused by increased resistance to aqueous humor outflow localized within the trabecular pathway (15,56). Abnormal accumulation of extracellular matrix (ECM) and/or extracellular material, which increases resistance to drainage of aqueous humor through the trabecular pathway, is believed to be partly responsible for the elevated intraocular pressure and primary open-angle glaucoma (24,28,49). The cellular mechanisms that regulate the production and turnover of ECM within the outflow pathway and how ECM turnover is linked to regulation of aqueous humor outflow through the trabecular meshwork (TM) are far from clearly understood (13,...

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Mechanistic basis of Rho GTPase-induced extracellular matrix synthesis in trabecular meshwork cells

Pattabiraman¹,

Rao

2010

American Journal of Physiology-Cell Physiology

174

222

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“…Honjo (2001) concluded that Y-27632 had reduced the intraocular pressure significantly in rabbits. Cellular changes of trabecular meshwork and ciliary muscle relaxation were considered to be the underlying mechanism [4,5,6].…”

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confidence: 99%

Rho- Kinase Inhibitor Y-27632 Decreases the Thickness of Trabecular Meshwork in Juvenile Rats Mod-el Injected with Sodium Hyaluronate

Vierlia

Wulandari²,

Sujuti³

et al. 2018

J.Trop.Life.Science

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Most glaucoma drugs lower the intraocular pressure (IOP) by decreasing the aqueous humor production and increasing the outflow through uveoscleral pathway. None of these drugs work mainly on increasing outflow through the trabecular pathway. Consequently, the experiment to develop glaucoma drugs directly target at the trabecular outflow pathway is highly required. The purpose of this study is to reveal the effect of rho-kinase inhibitor Y-27632 on the thickness of trabecular meshwork in juvenile rats model injected with sodium hyaluronate. This study was an experimental study with posttest only control group design. Twenty-four rats were included in this study. Each eye of the rat would be considered as one sample. Samples were divided into 6 groups, negative control group, positive control I group with intracameral sodium hyaluronate injection, positive control II group with topical Y-27632 10 mM, and three experimental groups with intracameral injection of sodium hyaluronate and Y-27632 10-1 mM, 1 mM, and 10 mM respectively. After the procedures all rats were sacrificed and enucleated. Trabecular meshwork tissue was stained with Hematoxilene-Eosin and evaluated under 400× microscopic magnification. Quantitative measurements were taken using computerized image analysis with dot slide program. There were significant statistic differences among the positive control I group and the experimental groups (p-value < 0.05) as well as the positive control II group and the experimental groups (p-value < 0.05). The highest mean of decreasing trabecular meshwork thickness was noted in the group given by sodium hyaluronate and Y-27632 10 mM with value of 118.42 µm. There was decreasing thickness of trabecular meshwork due to the effect of rho-kinase inhibitor Y-27632 in juvenile rats injected with sodium hyaluronate.

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Phase 1 Clinical Trials of a Selective Rho Kinase Inhibitor, K-115

et al. 2013

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; for the K-115 Clinical Study Group IMPORTANCE We conducted a series of phase 1 clinical trials to elucidate the efficacy and safety of the selective Rho kinase inhibitor K-115 as a candidate drug for the treatment of glaucoma. We report the intraocular pressure (IOP)-lowering effects and safety of K-115 based on our results. OBJECTIVE To study the IOP-lowering effects and safety of topical administration of a selective Rho kinase inhibitor, K-115, in healthy male adult volunteers. DESIGN AND SETTING Randomized, placebo-controlled, double-masked, group comparison phase 1 clinical trial. PARTICIPANTS In the initial single-instillation trial, 50 healthy volunteers were subdivided into groups and treated with placebo or K-115 in concentrations of 0.05%, 0.1%, 0.2%, 0.4%, and 0.8% in a stepwise manner. In the repeated-instillation trial, another 50 healthy volunteers were subdivided into groups and treated with placebo or K-115 in concentrations of 0.05%, 0.1%, 0.2%, 0.4%, and 0.8% twice daily for 7 days in a stepwise manner. MAIN OUTCOMES AND MEASURES In these clinical trials, the administration of eyedrops and associated examinations (including IOP measurements) were performed in a double-masked manner. RESULTS After single instillation of placebo or K-115 in concentrations of 0.05%, 0.1%, 0.2%, 0.4%, and 0.8%, the changes in IOP from baseline were −1.6 mm Hg for placebo and −3.4, −2.2, −2.6, −4.0, and −4.3 mm Hg, respectively, for the different concentrations 2 hours after instillation. Similar to the single-instillation trial, IOP reductions in the repeated-instillation trial were found after each instillation, with maximal reduction 1 to 2 hours after instillation. In the safety trial, slight to mild conjunctival hyperemia was found in more than half of the participants treated with K-115; it was found after each instillation and spontaneously resolved within 1½ hours. CONCLUSIONS AND RELEVANCE K-115 is a promising drug for lowering IOP in healthy adult eyes, with tolerable adverse events during at least short-term administration.

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The role of the actomyosin system in regulating trabecular fluid outflow

Cited by 110 publications

References 36 publications

Mechanistic basis of Rho GTPase-induced extracellular matrix synthesis in trabecular meshwork cells

Mechanistic basis of Rho GTPase-induced extracellular matrix synthesis in trabecular meshwork cells

Rho- Kinase Inhibitor Y-27632 Decreases the Thickness of Trabecular Meshwork in Juvenile Rats Mod-el Injected with Sodium Hyaluronate

Phase 1 Clinical Trials of a Selective Rho Kinase Inhibitor, K-115

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