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      Effects of Elevated Pressure on Prostanoid Receptor Gene Expression Levels in Human Trabecular Meshwork

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          The purpose of this study was to assess the effects of increased intraocular pressure on the expression levels of the prostanoid receptor genes (DP, EP<sub>1–4</sub>, FP, IP, TP) in the trabecular meshwork of human donor eyes. Anterior segments of human donor eyes were perfused in an ex vivo anterior segment perfusion system under different pressure regimes. The expression levels of the prostanoid receptors and of several housekeeping genes were assessed by non-competitive real-time quantitative polymerase chain reaction (Q-PCR). Perfusion of the anterior segments for 24 h at 10 mm Hg, followed by 24 h at 30 mm Hg, caused a significant decrease in the expression of the EP<sub>2</sub> receptor compared to a constant perfusion under 10 mm Hg. No significant changes were found for the other prostanoid receptor transcripts. When the pressure was raised to 30 mm Hg for only 1 or 3 h, no changes in the EP<sub>2</sub> receptor expression levels were evident. However, a transient DP and TP receptor expression increase was found after 1-hour perfusion at 30 mm Hg. Whether these changes in expression are part of a response of the trabecular meshwork cells in order to normalise intraocular pressure needs to be studied further.

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          Activation of a tissue-specific stress response in the aqueous outflow pathway of the eye defines the glaucoma disease phenotype.

          The glaucomas are a group of optic neuropathies comprising the leading cause of irreversible blindness worldwide. Elevated intraocular pressure due to a reduction in normal aqueous outflow is a major causal risk factor. We found that endothelial leukocyte adhesion molecule-1 (ELAM-1), the earliest marker for the atherosclerotic plaque in the vasculature, was consistently present on trabecular meshwork (TM) cells in the outflow pathways of eyes with glaucomas of diverse etiology. We determined expression of ELAM-1 to be controlled by activation of an interleukin-1 (IL-1) autocrine feedback loop through transcription factor NF-kappaB, and activity of this signaling pathway was shown to protect TM cells against oxidative stress. These findings characterize a protective stress response specific to the eye's aqueous outflow pathways and provide the first known diagnostic indicator of glaucomatous TM cells. They further indicate that common mechanisms contribute to the pathophysiology of the glaucomas and vascular diseases.
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            The mechanism of action of prostaglandins on uveoscleral outflow.

            It is generally accepted that prostaglandins (PGs) lower intraocular pressure by increasing uveoscleral outflow. The growing use of PGs to lower intraocular pressure has led to increased interest in the uveoscleral outflow. Uveoscleral outflow passes through extracellular spaces within the ciliary muscle and then through the suprachoroidal space to the posterior pole of the eye. Recent studies indicate that this reflects a direct effect of PGs on specific ciliary muscle prostanoid receptors. Activation of these receptors stimulates several linked responses, including cAMP formation and induction of c-Fos and c-Jun expression. These signals lead to increased biosynthesis of matrix metalloproteinases, a family of neutral proteinases that can cleave extracellular matrix molecules. These matrix metalloproteinases may initiate the alteration of collagens in the ciliary muscle to increase spaces among ciliary muscle fibers, thereby reducing hydraulic resistance in the uveoscleral outflow pathway.
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              Altered gene expression of prostacyclin synthase and prostacyclin receptor in the thoracic aorta of spontaneously hypertensive rats.

              The aim of this study was to evaluate the possible role of prostacyclin (PGI2) in the pathogenesis of hypertension in spontaneously hypertensive rats (SHR). Measurement of mRNA and protein levels of PGH synthase (PGHS)-1, PGI2 synthase and the PGI2 receptor, in the thoracic aorta was performed in SHR aged 5, 10, 20, and 40 weeks old and in age-matched normotensive Wistar-Kyoto (WKY) rats with a competitive polymerase chain reaction method and immunoblotting. Aortic production of 6-keto-PGF1 alpha, the main metabolite of PGI2, was also measured. Compared with age-matched WKY rats, PGHS-1 mRNA and protein levels in the thoracic aorta of SHR increased with age, reaching three- and twofold higher than WKY rats at 40 weeks old, respectively. PGI2 synthase mRNA and protein levels in SHR were significantly higher than in WKY rats at 20 and 40 weeks old. In contrast, PGI2 receptor mRNA levels in SHR were consistently lower than in WKY rats at all ages. These results provide evidence that hypertension elicits alterations in levels of arachidonic acid metabolites, including PGH2 and PGI2. They also suggest that the decreased expression of PGI2 receptor mRNA in prehypertensive SHR could be one of the causes of hypertension in SHR.

                Author and article information

                Ophthalmic Res
                Ophthalmic Research
                S. Karger AG
                October 2002
                11 October 2002
                : 34
                : 5
                : 314-318
                aNetherlands Ophthalmic Research Institute (NORI)-KNAW, Glaucoma Research Group and bDepartment of Ophthalmology, Lucas Andreas Ziekenhuis, Amsterdam, The Netherlands
                65606 Ophthalmic Res 2002;34:314–318
                © 2002 S. Karger AG, Basel

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                Page count
                Figures: 1, Tables: 1, References: 19, Pages: 5
                Original Paper


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