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J. Biol. Chem., Vol. 278, Issue 29, 27267-27277, July 18, 2003

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Comparison of Prostaglandin F₂, Bimatoprost (Prostamide), and Butaprost (EP₂ Agonist) on Cyr61 and Connective Tissue Growth Factor Gene Expression^*

Yanbin Liang, Chen Li, Victor M. Guzman, Albert J. Evinger, III, Charles E. Protzman, Achim H.-P. Krauss and David F. Woodward 

From the Allergan, Inc., Irvine, California 92612

Connective tissue growth factor (CTGF) and Cyr61 (cysteine-rich angiogenic protein 61) are members of the CCN gene family that encode multifunctional, extracellular matrix-associated signaling proteins. Because the mechanism of action of certain anti-glaucoma drugs involves extracellular matrix remodeling of ocular ciliary muscle, with a resultant increase in drainage of aqueous humor from the eye, we compared the effects of three pharmacologically distinct ocular hypotensive agents on Cyr61 and CTGF gene expression. Thus, prostaglandin F₂ (PGF₂) (FP receptor agonist), Butaprost (EP₂ receptor agonist), and Bimatoprost (a prostamide) were compared. Using Affymetrix gene chip technology, we first identified that PGF₂ dramatically up-regulated Cyr61 and CTGF mRNA expression in HEK 293/EBNA cells (hFP-HEK 293/EBNA). Northern blot further confirmed the Cyr61 and CTGF up-regulation is in a dose- and time-dependent manner. PGF₂-induced up-regulation of Cyr61 appeared to exclusively involve the Rho pathway, and up-regulation of CTGF was via multiple intracellular pathways. Because prostamide receptors are, to date, defined only at the pharmacological level, Bimatoprost effects on Cyr61 and CTGF were studied in the isolated feline iris sphincter preparation, a tissue highly responsive to prostamides. Both PGF₂ and Bimatoprost up-regulated Cyr61 mRNA expression in the cat iris tissue. Only PGF₂ up-regulated CTGF mRNA expression in the cat iris. Therefore, PGF₂ and Bimatoprost appear to interact with different receptors populations in the cat iris, according to their markedly different effects on CTGF. Activation of prostaglandin EP₂ receptors (G_s-coupled) also up-regulated Cyr61 but not CTGF mRNA expression in the isolated cat iris. Similar data were observed in human primary ciliary smooth muscle cells. Thus, despite quite different signal transduction pathways, FP receptor stimulation up-regulates CTGF and Cyr61. The prostamide analog Bimatoprost and an EP₂-selective agonist affects only Cyr61.

Received for publication, January 30, 2003 , and in revised form, April 28, 2003.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom Correspondence should be addressed: Dept. of Biological Science, Allergan, Inc., 2525 Dupont Dr., Irvine, CA 92612. Tel.: 714-246-5490; Fax: 714-246-5578; E-mail: Woodward_David{at}Allergan.com.

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