Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0595921 (intraocular pressure)
 11,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The control of smooth muscle contraction is an important factor in maintaining normal intraocular pressure. However, the specific factors causing changes in control by phosphorylation/dephosphorylation schemes in the eye are not well-defined. The purposes of this experiment were to (i) determine the localization of ROCK (Rho-associated, coiled coil-forming kinase) in monkey and rabbit eye tissues and (ii) measure phosphorylation of ROCK substrate during trabecular meshwork or ciliary muscle contraction induced by carbachol. We found that mRNAs for both ROCK I and II were expressed in most eye tissues from rabbit and monkey. Proteins for ROCK I and II were present in all eye tissues studied except lens. When trabecular meshwork or ciliary muscle were incubated with carbachol to induce contraction, phosphorylation of the myosin-binding subunit (MBS) of myosin phosphatase, a substrate for ROCK, started within 1 min and continued for at least 1 h. This phosphorylation was well correlated with contraction of trabecular meshwork or ciliary muscle. These results suggested that ROCK might regulate contraction of trabecular meshwork or ciliary muscle through phosphorylation of MBS of myosin phosphatase.
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PMID:Involvement of phosphorylation of myosin phosphatase by ROCK in trabecular meshwork and ciliary muscle contraction. 1160 42

There is clinical and experimental evidence that elevated intraocular pressure (IOP), a mechanical stress, is involved in the pathogenesis of glaucomatous optic neuropathy. The mechanism by which astrocytes in the optic nerve head (ONH) respond to changes in IOP is under study. Gene transcription by ONH astrocytes exposed either to 60 mmHg hydrostatic pressure (HP) or control ambient pressure (CP) for 6, 24, and 48 h was compared using Affymetrix GeneChip microarrays to identify HP-responsive genes. Data were normalized across arrays within each gene. A linear regression model applied to test effect of time and HP on changes in expression level identified 596 genes affected by HP over time. Using GeneSpring analysis we selected genes whose average expression level increased or decreased more than 1.5-fold at 6, 24, or 48 h. Expression of selected genes was confirmed by real-time RT-PCR; protein levels were detected by Western blot. Among the genes highly responsive to HP were those involved in signal transduction, such as Rho nucleotide exchange factors, Ras p21 protein activator, tyrosine kinases and serine threonine kinases, and genes involved in transcriptional regulation, such as c-Fos, Egr2, and Smad3. Other genes that increased expression included ATP-binding cassettes, solute carriers, and genes associated with lipid metabolism. Among the genes that decreased expression under HP were genes encoding for dual activity phosphatases, transcription factors, and enzymes involved in protein degradation. These HP-responsive genes may be important in the establishment and maintenance of the ONH astrocyte phenotype under conditions of elevated IOP in glaucoma.
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PMID:DNA microarray analysis of gene expression in human optic nerve head astrocytes in response to hydrostatic pressure. 1474 62

Aqueous outflow in the conventional outflow pathway is regulated by the contraction and relaxation of the ciliary muscle (CM) and the trabecular meshwork (TM). Rho-associated coiled coil-forming protein kinase (ROCK) is thought to regulate actomyosin-based contractility in many types of cells by phosphorylation of ROCK substrates. In animal models, ROCK inhibitor Y-39983 relaxed CM and TM and decreased intraocular pressure (IOP). Thus, ROCK is implicated in the regulation of aqueous outflow and IOP. However, the site of action of ROCK in monkey and man is unknown. In the present communication, RT-PCR analysis of monkey tissues showed higher levels of mRNAs for ROCK and ROCK substrates in TM compared to CM. Human TM also showed higher levels of mRNAs for ROCK and ROCK substrates compared to CM. Differences between TM and CM in human were not as high as in monkey. ROCK inhibitor Y-39983 led to a dose-dependent relaxation of carbachol-induced, contracted TM from monkey. In contrast, Y-39983 was only slightly effective in relaxing CM. Our results suggested that TM was one of the major sites for regulating IOP by ROCK. ROCK inhibitor Y-39983 might be a candidate drug for lowering IOP by increasing conventional outflow and producing fewer side effects on accommodation and miosis.
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PMID:Contribution of ROCK in contraction of trabecular meshwork: proposed mechanism for regulating aqueous outflow in monkey and human eyes. 1568 86

Hexahydro-1-(isoquinoline-5-sulfonyl)-1H-1,4-diazepine, HA-1077, is a known selective inhibitor of Rho-kinase. Although its IC(50) value against Rho-kinase is more than 10 times lower than those for kinases such as PKA, PKB, PKC, PKG, MLCK, CaMKII and others, the molecule still retains relative potent inhibition activities against these kinases. In order to produce highly specific Rho-kinase inhibitors, several HA-1077 analogs were synthesized and their kinase inhibition properties evaluated. (S)-Hexahydro-1-(4-ethenylisoquinoline-5-sulfonyl)-2-methyl-1H-1,4-diazepine was found to be a potent Rho-kinase inhibitor. The IC50 value against Rho-kinase was 6 nM, while those against other kinases remained at almost the same level as that of HA-1077. Furthermore, we designed HA-1077 analogs on the basis of the complex structure of PKA and HA-1077. Amongst these, (S)-hexahydro-4-glycyl-2-methyl-1-(4-methylisoquinoline-5-sulfonyl)-1H-1,4-diazepine and other glycine derivatives were found to be highly specific Rho-kinase inhibitors. These Rho-kinase specific inhibitors were applied to rabbit ocular hypertensive models and were shown to reduce intraocular pressure. These results demonstrate that the new 5-isoquinolinesulfonylamides are not only potent ROCK selective compounds, but are also useful compounds for clinical applications.
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PMID:Development of specific Rho-kinase inhibitors and their clinical application. 1621 95

A number of genes associated with life phenomena have been identified by the achievement of genome projects. As both comprehensive analysis and methods for investigation of specific genes have been developed, we can understand the pathogenesis of ocular diseases and develop novel medical treatments based upon detailed information on molecular mechanisms. In our review article, we focused on three vision-threatening ocular diseases; glaucoma, age-related macular degeneration (AMD) and proliferative vitreoretinopathy (PVR), and discussed the potential and problems related to retinal regenerative therapy. Regarding glaucoma, we investigated the relationships between aqueous humor and cell components in the aqueous outflow route. We have revealed that the Rho-Rho-associated coiled-coil-forming protein kinase (ROCK) signal transduction pathway participates in regulation of the aqueous outflow route, and that ROCK inhibitors and several protein kinase inhibitors exert intraocular pressure-lowering effects. Also, we conducted a series of investigations on familial amyloidotic polyneuropathy (FAP), as a representative secondary glaucoma caused by genetic mutations in a single gene. We reviewed the clinical features of ocular complications derived from FAP, their molecular mechanisms and possibilities for the development of novel medical treatments. In addition, we discussed a novel therapeutic concept, "neuroprotection", and showed the potential of some drugs as candidates for the neuroprotective treatment of glaucoma. Against AMD, we have performed a series of experiments from the viewpoint of similarity with atherosclerotic lesions. We have shown the molecular mechanisms of AMD associated with up-regulated expression of scavenger receptors and the interaction between leukocytes and vascular endothelial cells. Furthermore, in the pathogenesis of PVR, we described the role of epithelial-mesenchymal transition in retinal pigment epithelial cells and demonstrated the usefulness of enzymatic vitrectomy. Although retinal regenerative therapy has attracted much attention from global investigators, we pointed out its limitation for clinical application, and developed researches on efficient culture method using physiologically active factors for proliferating retinal stem cells with multi-potentiality, differentiation of the transplanted progenitor cells, and axon guidance of neurons by extracellular matrices.
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PMID:[New understanding and development of medical treatments for ocular diseases based upon molecular mechanisms]. 1640 90

Rho kinase (ROCK1 and ROCK2) is a serine/threonine kinase that serves as an important downstream effector of Rho GTPase, and plays a critical role in regulating the contractile tone of smooth muscle tissues in a calcium-independent manner. Several lines of experimental evidence indicate that modulating ROCK activity within the aqueous humor outflow pathway using selective inhibitors could achieve very significant benefits for the treatment of increased intraocular pressure in patients with glaucoma. The rationale for such an approach stems from experimental data suggesting that both ROCK and Rho GTPase inhibitors can increase aqueous humor drainage through the trabecular meshwork, leading to a decrease in intraocular pressure. In addition to their ocular hypotensive properties, inhibitors of both ROCK and Rho GTPase have been shown to enhance ocular blood flow, retinal ganglion cell survival and axon regeneration. These properties of the ROCK and Rho GTPase inhibitors indicate that targeting the Rho GTPase/ROCK pathway with selective inhibitors represents a novel therapeutic approach aimed at lowering increased intraocular pressure in glaucoma patients.
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PMID:Rho GTPase/Rho kinase inhibition as a novel target for the treatment of glaucoma. 1751 12

Impaired drainage of aqueous humor through the trabecular meshwork (TM) culminating in increased intraocular pressure is a major risk factor for glaucoma, a leading cause of blindness worldwide. Regulation of aqueous humor drainage through the TM, however, is poorly understood. The role of RhoA GTPase-mediated actomyosin organization, cell adhesive interactions, and gene expression in regulation of aqueous humor outflow was investigated using adenoviral vector-driven expression of constitutively active mutant of RhoA (RhoAV14). Organ-cultured anterior segments from porcine eyes expressing RhoAV14 exhibited significant reduction of aqueous humor outflow. Cultured TM cells expressing RhoAV14 exhibited a pronounced contractile morphology, increased actin stress fibers, and focal adhesions and increased levels of phosphorylated myosin light chain (MLC), collagen IV, fibronectin, and laminin. cDNA microarray analysis of RNA extracted from RhoAV14-expressing human TM cells revealed a significant increase in the expression of genes encoding extracellular matrix (ECM) proteins, cytokines, integrins, cytoskeletal proteins, and signaling proteins. Conversely, various ECM proteins stimulated robust increases in phosphorylation of MLC, paxillin, and focal adhesion kinase and activated Rho GTPase and actin stress fiber formation in TM cells, indicating a potential regulatory feedback interaction between ECM-induced mechanical strain and Rho GTPase-induced isometric tension in TM cells. Collectively, these data demonstrate that sustained activation of Rho GTPase signaling in the aqueous humor outflow pathway increases resistance to aqueous humor outflow through the trabecular pathway by influencing the actomyosin assembly, cell adhesive interactions, and the expression of ECM proteins and cytokines in TM cells.
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PMID:Novel molecular insights into RhoA GTPase-induced resistance to aqueous humor outflow through the trabecular meshwork. 1879 48

Primary open angle glaucoma (POAG) is a major blindness-causing disease, characterized by elevated intraocular pressure due to an insufficient outflow of aqueous humor. The trabecular meshwork (TM) lining the aqueous outflow pathway modulates the aqueous outflow facility. TM cell adhesion, cell-matrix interactions, and factors that influence Rho signaling in TM cells are thought to play a pivotal role in the regulation of aqueous outflow. In a recent study, we demonstrated that galectin-8 (Gal8) modulates the adhesion and cytoskeletal arrangement of TM cells and that it does so through binding to beta(1) integrins and inducing Rho signaling. The current study is aimed at the characterization of the mechanism by which Gal8 mediates TM cell adhesion and spreading. We demonstrate here that TM cells adhere to and spread on Gal8-coated wells but not on galectin-1 (Gal1)- or galectin-3 (Gal3)-coated wells. The adhesion of TM cells to Gal8-coated wells was abolished by a competing sugar, beta-lactose, but not by a noncompeting sugar, sucrose. Also, a trisaccharide, NeuAcalpha2-3Galbeta1-4GlcNAc, which binds specifically to the N-CRD of Gal8, inhibited the spreading of TM cells to Gal8-coated wells. In contrast, NeuAcalpha2-6Galbeta1-4GlcNAc which lacks affinity for Gal8 had no effect. Affinity chromatography of cell extracts on a Gal8-affinity column and binding experiments with plant lectins, Maakia Amurensis and Sambucus Nigra, revealed that alpha(3)beta(1), alpha(5)beta(1), and alpha(v)beta(1) integrins are major counterreceptors of Gal8 in TM cells and that TM cell beta(1) integrins carry predominantly alpha2-3-sialylated glycans, which are high-affinity ligands for Gal8 but not for Gal1 or Gal3. These data lead us to propose that Gal8 modulates TM cell adhesion and spreading, at least in part, by interacting with alpha2-3-sialylated glycans on beta(1) integrins.
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PMID:The role of integrin glycosylation in galectin-8-mediated trabecular meshwork cell adhesion and spreading. 1884 83

The medical treatment of glaucoma has undergone significant development in recent years. Research in this field is focused on improving pre-existing drugs and on the development of new molecules. In relation to commercial drugs, there is a trend to improve local tolerance, using less toxic preservatives as in the case of sofZIA in travoprost, and eliminating the preservatives as in tafluprost. The development of new, fixed combinations of commercial drugs could also enhance their administration and therapeutic compliance. There is also intense research activity in the search for new therapeutic groups for glaucoma treatment. Calcium channel-blockers such as lomerizine do not seem to affect systemic hypotension, while topical calcium-blockers like flunarizine and iganidipine are also under research. Endothelin 1 antagonists such as sulfisoxazole and bunazosine could be also useful in the treatment of glaucoma. In the renin angiotensin system, angiotensin (1-7) and olmesartan are under investigation for use in glaucoma patients. Trabecular drugs such as Rho-kinase inhibitors could be effective on the pathogenic mechanism of primary open angle glaucoma. Finally, topical mifepristone, an antagonist of glucocorticoid receptors, is under evaluation for corticosteroid-induced elevated intraocular pressure (Arch Soc Esp Oftalmol 2009; 84: 491-500).
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PMID:[New developments in glaucoma medical treatment]. 1990 93

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, alpha-smooth muscle actin (alpha-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-beta(2), known to increase resistance to aqueous humor outflow and activate Rho/Rho kinase signaling. RhoAV14, lysophosphatidic acid, and TGF-beta(2) stimulated significant increases in Erk1/2 phosphorylation, paralleled by profound increases in fibronectin, serum response factor (SRF), and alpha-SMA expression. Treatment of RhoA-activated TM cells with inhibitors of Rho kinase or Erk, on the other hand, decreased fibronectin and alpha-SMA levels. Although suppression of SRF expression (both endogenous and RhoA, TGF-beta(2)-stimulated) via the use of short hairpin RNA decreased alpha-SMA levels, fibronectin was unaffected. Conversely, fibronectin induced alpha-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 alpha-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.
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PMID:Mechanistic basis of Rho GTPase-induced extracellular matrix synthesis in trabecular meshwork cells. 1994 66


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