Effects of Cholesterol-Lowering Statins on the Aqueous Humor Outflow Pathway

Song, Julia; Deng, Peifeng; Stinnett, Sandra S.; Epstein, David L.; Rao, Ponugoti Vasantha

doi:10.1167/iovs.04-0776

Cited by 85 publications

(67 citation statements)

References 50 publications

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“…Porcine TM cells were isolated by collagenase as described previously. 23 Porcine TM cells were cultured in Dulbecco's modified Eagle medium (DMEM; WAKO Pure Chemical Industries, Osaka, Japan) containing 10% fetal bovine serum (FBS; Hyclone Laboratories, Logan, UT), 2 mM glutamine, 100 U/mL penicillin, 100 lg/mL streptomycin, and 0.5 lg/mL amphotericin B at 378C in 5% CO 2 , and TM cells between passages 3 and 5 were used for all the experiments in our study.…”

Section: Cell Culturementioning

confidence: 99%

Involvement of RhoA/Rho-Associated Kinase Signal Transduction Pathway in Dexamethasone-Induced Alterations in Aqueous Outflow

Fujimoto

Inoue

Kameda

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. We investigated the involvement of the RhoA/Rho kinase (ROCK) signal transduction pathway in dexamethasone (DEX)-induced changes in aqueous outflow.METHODS. Using trabecular meshwork (TM) and Schlemm's canal endothelial (SCE) cells, RhoA activation was evaluated with a pull-down assay and myosin light chain phosphorylation was evaluated by Western blot analysis. Outflow facility was measured in perfused porcine anterior segment organ cultures treated with DEX and/or Y-27632, a selective ROCK inhibitor. The barrier function of the cultured cells on a micropore filter was evaluated by measuring the transendothelial electrical resistance. Collagen, fibronectin, and integrin mRNA expression levels were evaluated by quantitative realtime RT-PCR. RESULTS.Relative RhoA activities increased following stimulation with 100 nM DEX in TM and SCE cells. Perfusion with DEX decreased outflow facility by 31.9 6 14.3% compared to controls at 24 hours, but not by 50 lM Y-27632 in addition to DEX. The transendothelial electrical resistance of the SCE cell monolayer was increased by 48.6 6 6.4% and 5.3 6 5.0% following DEX treatments without and with 10 lM Y-27632, respectively, compared to controls. In TM cells, the mRNA expressions of COL4A1 and fibronectin were increased significantly by DEX treatment, but combined treatment with Y-27632 and DEX significantly inhibited the increase in COL4A1and fibronectin expression.CONCLUSIONS. Activation of the Rho/ROCK pathway in SCE cells contributes to the mechanism of DEX-induced changes in aqueous outflow. (Invest Ophthalmol Vis Sci. 2012;53:7097-7108) DOI:10.1167/iovs.12-9989 S teroid-induced ocular hypertension is an important clinical problem related to the use of glucocorticoid therapy for many types of disorders. Already in 1963, Armaly reported that the widely used glucocorticoid dexamethasone (DEX) induces changes in intraocular pressure (IOP) and fluid dynamics in normal eyes, and that DEX-induced IOP elevation is observed more frequently in the patients with glaucoma. 1-3 IOP levels often are quite high in patients with steroid-induced ocular hypertension, and prolonged IOP elevation sometimes results in the loss of visual function. Topical administration of triamcinolone acetonide (TA), a synthetic corticosteroid, is considered a useful therapeutic modality for the management of intraocular inflammatory and/or proliferative diseases. The increasing number of patients treated with TA by intravitreous and/or sub-Tenon injections, however, has attracted the attention of ophthalmologists because of the potential risk of steroid-induced ocular hypertension. 4,5The mechanisms underlying steroid-induced ocular hypertension are associated with abnormal changes in the conventional outflow pathway caused by steroid administration. Some researchers attribute the decreased outflow to an accumulation of extracellular matrix (ECM) components, such as glycosaminoglycans, collagens, fibronectin, and elastin. [6][7][8][9] Others have proposed that the decreased outflow is due to decrea...

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Section: Cell Culturementioning

confidence: 99%

Involvement of RhoA/Rho-Associated Kinase Signal Transduction Pathway in Dexamethasone-Induced Alterations in Aqueous Outflow

Fujimoto

Inoue

Kameda

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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“…Although the applicability of statins on age-related macular degeneration is still under investigation (49), statins are shown to have protective effects on primary open-angle glaucoma, a major cause of blindness (50). The regulation of the intraocular pressure (IOP) within a physiological range is of great clinical importance.…”

Section: Discussionmentioning

confidence: 99%

“…The regulation of the intraocular pressure (IOP) within a physiological range is of great clinical importance. Statins are reported to downregulate the IOP by increasing aqueous humor outflow via the inhibition of Rho/Rho-kinase pathway in the trabecular meshwork and the ciliary body (50).…”

Section: Discussionmentioning

confidence: 99%

Potent Inhibition of Cicatricial Contraction in Proliferative Vitreoretinal Diseases by Statins

et al. 2008

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OBJECTIVE-Despite tremendous progress in vitreoretinal surgery, certain postsurgical complications limit the success in the treatment of proliferative vitreoretinal diseases (PVDs), such as proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR). One of the most significant complications is the cicatricial contraction of proliferative membranes, resulting in tractional retinal detachment and severe vision loss. Novel pharmaceutical approaches are thus urgently needed for the management of these vision-threatening diseases. In the current study, we investigated the inhibitory effects of statins on the progression of PVDs.RESEARCH DESIGN AND METHODS-Human vitreous concentrations of transforming growth factor-␤2 (TGF-␤2) were measured by enzyme-linked immunosorbent assay. TGF-␤2-and vitreous-dependent phosphorylation of myosin light chain (MLC), a downstream mediator of Rho-kinase pathway, and collagen gel contraction simulating cicatrical contraction were analyzed using cultured hyalocytes. Inhibitory effects of simvastatin on cicatrical contraction were assessed both in vitro and in vivo.RESULTS-Human vitreous concentrations of TGF-␤2 were significantly higher in the samples from patients with PVD compared with those without PVD. Simvastatin inhibited TGF-␤2-dependent MLC phosphorylation and gel contraction in a dose-and time-dependent manner and was capable of inhibiting translocation of Rho protein to the plasma membrane in the presence of TGF-␤2. Vitreous samples from patients with PVD enhanced MLC phosphorylation and gel contraction, whereas simvastatin almost completely inhibited these phenomena. Finally, intravitreal injection of simvastatin dose-dependently prevented the progression of diseased states in an in vivo model of PVR.CONCLUSIONS-Statins might have therapeutic potential in the prevention of PVDs.

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“…Similar fi ndings of the statin-induced MLC dephosphorylation have been reported in other cell types, including vascular endothelium. 9,39,40 In our recent study, we have also observed that microtubule disassembly induced by thrombin can be suppressed by pretreatment with paclitaxel, a microtubule stabilizing agent. 41 Similar barrier dysfunction involving microtubule disassembly is well known in vascular endothelium as well.…”

Section: Effect Of Lovastatin On Status Of Mypt1 Phosphorylationmentioning

confidence: 85%

Lovastatin Inhibits the Thrombin-Induced Loss of Barrier Integrity in Bovine Corneal Endothelium

Shivanna

Jalimarada

Srinivas

2010

Journal of Ocular Pharmacology and Therapeutics

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Purpose: Increased actomyosin contraction of the dense band of actin cytoskeleton at the apical junctional complex (perijunctional actomyosin ring, PAMR) breaks down the barrier integrity of corneal endothelium. This study has investigated the effi cacy of statins, which inhibit activation of RhoA, in opposing the thrombininduced loss of barrier integrity of monolayers of cultured bovine corneal endothelium. Methods: Myosin light chain (MLC) phosphorylation, a biochemical measure of actomyosin contraction, was assayed by urea-glycerol gel electrophoresis, followed by western blot analysis. The locus of MLC phosphorylation and changes in the organization of the PAMR were visualized by immunostaining. Phosphorylation of MYPT1, a regulatory subunit of myosin light-chain phosphatase (MLCP), was assessed by Western blot analysis to determine down-regulation of RhoA. The barrier integrity was assessed in terms of trans-endothelial electrical resistance (TER), and further confi rmed by determining permeability to FITC dextran (10 kDa) and distribution of ZO-1, a marker of tight junctional assembly. Results: Lovastatin, a prototype of lipophilic statins, induced MLC dephosphorylation under basal conditions. It opposed increase in phosphorylation of MLC and MYPT1 in response to thrombin and nocodazole, agents known to activate RhoA in the endothelium. Pretreatment with the statin opposed the thrombin-and nocodazole-induced disruption of the PAMR and the thrombin-induced decline in TER. Lovastatin also opposed the thrombin-and nocodazole-induced increase in permeability to FITC dextran and redistribution of ZO-1. However, upon supplementation with GGPP (geranylgeranyl pyrophosphate), lovastatin failed to oppose the effects of thrombin and nocodazole on the PAMR, ppMLC, and ZO-1 distribution. Conclusions: Lovastatin attenuates RhoA activation in the corneal endothelium presumably by reducing its isoprenylation. This underlies the suppression of the thrombin-induced loss in barrier integrity of the corneal endothelium.

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Effects of Cholesterol-Lowering Statins on the Aqueous Humor Outflow Pathway

Cited by 85 publications

References 50 publications

Involvement of RhoA/Rho-Associated Kinase Signal Transduction Pathway in Dexamethasone-Induced Alterations in Aqueous Outflow

Involvement of RhoA/Rho-Associated Kinase Signal Transduction Pathway in Dexamethasone-Induced Alterations in Aqueous Outflow

Potent Inhibition of Cicatricial Contraction in Proliferative Vitreoretinal Diseases by Statins

Lovastatin Inhibits the Thrombin-Induced Loss of Barrier Integrity in Bovine Corneal Endothelium

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