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Global changes in optic nerve head gene expression after exposure to elevated intraocular pressure in a rat glaucoma model.

ABSTRACT: In glaucoma, the optic nerve head (ONH) is the likely site of initial injury and elevated intraocular pressure (IOP) is the best-known risk factor. This study determines global gene expression changes in the pressure-injured ONH.Unilateral sustained IOP elevation (glaucoma, n = 46) or optic nerve transection (n = 10) was produced in rats. ONHs were removed, and the retrobulbar optic nerves were graded for degeneration. Gene expression in the glaucomatous ONH with extensive injury was compared with that in the fellow ONH (n = 6/group), by using cDNA microarrays. Data from 12 arrays were normalized, significant differences in gene expression determined, and significantly affected gene classes identified. For the remaining ONH, grouped by experimental condition and degree of injury, quantitative reverse transcriptase-PCR (qPCR) and ANOVA were used to compare selected message levels.Microarray analysis identified more than 2000 significantly regulated genes. For 225 of these genes, the changes were greater than twofold. The most significantly affected gene classes were cell proliferation, immune response, lysosome, cytoskeleton, extracellular matrix, and ribosome. A 2.7-fold increase in ONH cellularity confirmed glaucoma model cell proliferation. By qPCR, increases in levels of periostin, collagen VI, and transforming growth factor beta1 were linearly correlated to the degree of IOP-induced injury. For cyclinD1, fibulin 2, tenascin C, TIMP1, and aquaporin-4, correlations were significantly nonlinear, displaying maximum change with focal injury.In the ONH, pressure-induced injury results in cell proliferation and dramatically altered gene expression. For specific genes, expression levels were most altered by focal injury, suggesting that further array studies may identify initial, and potentially injurious, altered processes.

SUBMITTER: Johnson EC

PROVIDER: S-EPMC1950563 | biostudies-literature | 2007 Jul

REPOSITORIES: biostudies-literature

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Global changes in optic nerve head gene expression after exposure to elevated intraocular pressure in a rat glaucoma model.

Johnson Elaine C EC Jia Lijun L Cepurna William O WO Doser Thomas A TA Morrison John C JC

Investigative ophthalmology & visual science 20070701 7

<h4>Purpose</h4>In glaucoma, the optic nerve head (ONH) is the likely site of initial injury and elevated intraocular pressure (IOP) is the best-known risk factor. This study determines global gene expression changes in the pressure-injured ONH.<h4>Methods</h4>Unilateral sustained IOP elevation (glaucoma, n = 46) or optic nerve transection (n = 10) was produced in rats. ONHs were removed, and the retrobulbar optic nerves were graded for degeneration. Gene expression in the glaucomatous ONH with ...[more]

PMID: 17591886

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Project description:Intraocular pressure (IOP) is an important risk factor for glaucoma, and the response of the ONH and surrounding tissues to elevated IOP are often investigated to better understand pathophysiology. In vivo structure including that of the optic nerve head (ONH) and surrounding tissue of the eye are often assessed using optical coherence tomography (OCT). With advances in OCT technology, both large vessels and capillaries can be imaged non-invasively (OCT Angiography). Because a significant portion of retinal thickness is comprised of vasculature, the purpose of the current study was to investigate OCT structural and vascular changes in healthy non-human primate eyes with systematic graded increases and decreases in IOP. Six healthy animals with no previous experimental intervention were used. The pressure in the anterior chamber was adjusted from 10?mmHg to 60?mmHg and back to 10?mmHg in 10?mmHg steps every 10?min. Using optical coherence tomography (OCT), retinal nerve fiber layer (RNFL) thickness, minimum rim width (MRW), Bruch's membrane opening (BMO) size and relative height, anterior lamina cribrosa surface (ALCS) depth, choroidal thickness, and angiography (OCTA) were quantified. With IOP challenge there were significant changes in all morphological measures quantified (p?<?0.01) other than BMO size (p?=?0.30) and RNFL thickness (p?=?0.29). Specifically, the position of the BMO was sensitive to both an increase and decease in IOP. The inner retinal capillary density gradually decreased with increasing IOP, reaching statistical significance when pressure exceeded 50?mmHg, but returned when IOP was reduced. The average choroidal thickness around the ONH decreased for elliptical annuli 500-1000??m and 1000-1500??m, from the BMO, with increasing IOP (p?<?0.01). For the 1000-1500??m annulus, choroid thickness did not return to baseline with IOP reduction. Similarly, the MRW decreased with increase in IOP, but with pressure reduction did not return, and at the final 10?mmHg time point was thinner than at baseline (p?<?0.01). The results from this experiment illustrate differences in ONH neural rim tissue, RNFL and vessel density changes with acute IOP challenge. Overall, vessel collapse could not completely account for changes in RNFL or ONH MRW thickness. The study supports the hypothesis neural rim compression may be an important part of IOP-induced damage.

Project description:PURPOSE: To investigate factors associated with changes in optic nerve head (ONH) topography after acute intraocular pressure (IOP) reduction in patients with primary open-angle glaucoma (POAG). METHODS: Untreated POAG patients (IOP >21 mm Hg) were prospectively enrolled. Systemic and ocular information were collected, including central corneal thickness (CCT) and corneal hysteresis (CH). All patients underwent confocal scanning laser ophthalmoscopy and tonometry (Goldmann) before and 1 h after pharmacological IOP reduction. The mean of three measurements was considered for analysis. Changes in each ONH topographic parameter were assessed (one eye was randomly selected), and those that changed significantly were correlated with patient's systemic and ocular characteristics. RESULTS: A total of 42 patients were included (mean age, 66.7 ± 11.8 years). After a mean IOP reduction of 47.3 ± 11.9%, significant changes were observed in cup area and volume, and in rim area and volume (P < 0.01), but not in mean cup depth (P = 0.80). Multiple regression analysis (controlling for baseline IOP and magnitude of IOP reduction) showed that CH (r(2) = 0.17, P < 0.01) and diabetes diagnosis (r(2) ≥ 0.21, P < 0.01) were negatively correlated with the magnitude of changes in ONH parameters, whereas the cup-to-disc ratio was positively correlated (r(2) = 0.30, P < 0.01). Age, race, disc area, and CCT were not significant (P ≥ 0.12). Including all significant factors in a multivariable model, only the presence of diabetes remained significantly associated with all ONH parameters evaluated (P < 0.01). CONCLUSIONS: Different systemic and ocular factors, such as diabetes, CH, and the relative size of the cup, seem to be associated with the magnitude of changes in ONH topography after acute IOP reduction in POAG patients. These associations partially explain the ONH changes observed in these patients and suggest that other factors are possibly implicated in an individual susceptibility to IOP.

Dataset Information

Global changes in optic nerve head gene expression after exposure to elevated intraocular pressure in a rat glaucoma model.

Publications

Global changes in optic nerve head gene expression after exposure to elevated intraocular pressure in a rat glaucoma model.

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