title: Regulation of trabecular meshwork cell contraction and intraocular pressure by miR-200c.
abstract: Lowering intraocular pressure (IOP) delays or prevents the loss of vision in primary open-angle glaucoma (POAG) patients with high IOP and in those with normal tension glaucoma showing progression. Abundant evidence demonstrates that inhibition of contractile machinery of the trabecular meshwork cells is an effective method to lower IOP. However, the mechanisms involved in the regulation of trabecular contraction are not well understood. Although microRNAs have been shown to play important roles in the regulation of multiple cellular functions, little is known about their potential involvement in the regulation of IOP. Here, we showed that miR-200c is a direct postranscriptional inhibitor of genes relevant to the physiologic regulation of TM cell contraction including the validated targets Zinc finger E-box binding homeobox 1 and 2 (ZEB1 and ZEB2), and formin homology 2 domain containing 1 (FHOD1), as well as three novel targets: lysophosphatidic acid receptor 1 (LPAR1/EDG2), endothelin A receptor (ETAR), and RhoA kinase (RHOA). Consistently, transfection of TM cells with miR-200c resulted in strong inhibition of contraction in collagen populated gels as well as decreased cell traction forces exerted by individual TM cells. Finally, delivery of miR-200c to the anterior chamber of living rat eyes resulted in a significant decrease in IOP, while inhibition of miR-200c using an adenoviral vector expressing a molecular sponge led to a significant increase in IOP. These results demonstrate for the first time the ability of a miRNA to regulate trabecular contraction and modulate IOP in vivo, making miR-200c a worthy candidate for exploring ways to alter trabecular contractility with therapeutic purposes in glaucoma.
authors.affiliation: Department of Ophthalmology, Duke University, Durham, North Carolina, United States of America.
authors.forename: Coralia
authors.initials: C
authors.lastname: Luna
authors.forename: Guorong
authors.initials: G
authors.lastname: Li
authors.forename: Jianyong
authors.initials: J
authors.lastname: Huang
authors.forename: Jianming
authors.initials: J
authors.lastname: Qiu
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.forename: Fan
authors.initials: F
authors.lastname: Yuan
authors.forename: David L
authors.initials: DL
authors.lastname: Epstein
authors.forename: Pedro
authors.initials: P
authors.lastname: Gonzalez
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D007429:Intraocular Pressure / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics*; D051381:Rats; D044022:Receptor, Endothelin A / Q000235:genetics; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics; D014129:Trabecular Meshwork / Q000166:cytology* / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D044022:Receptor, Endothelin A; D049368:Receptors, Lysophosphatidic Acid; D020742:rhoA GTP-Binding Protein