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J. Biol. Chem., Vol. 281, Issue 17, 11864-11871, April 28, 2006

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Glyoxalase I Is Critical for Human Retinal Capillary Pericyte Survival under Hyperglycemic Conditions^*

Antonia G. Miller, Dawn G. Smith, Manjunatha Bhat^¶, and Ram H. Nagaraj, Recipient of a Research to Prevent Blindness Lew R. Wasserman Merit Award^||1

From the Departments of Ophthalmology and ^||Pharmacology and Visual Sciences Research Center, Case Western Reserve University, Cleveland, Ohio 44106 and ^¶Center for Anesthesiology Research, Cleveland Clinic Foundation, Cleveland, Ohio 44195

Retinal capillary pericytes undergo premature death, possibly by apoptosis, during the early stages of diabetic retinopathy. The -oxoaldehyde, methylglyoxal (MGO), has been implicated as a cause of cell damage in diabetes. We have investigated the role of MGO and its metabolizing enzyme, glyoxalase I, in high glucose-induced apoptosis (annexin V binding) of human retinal pericyte (HRP). HRP incubated with high glucose (30 mM D-glucose) for 7 days did not undergo apoptosis despite accumulation of MGO. However, treatment with a combination of high glucose and S-p-bromobenzylglutathione cyclopentyl diester, a competitive inhibitor of glyoxalase I, resulted in apoptosis along with a dramatic increase in MGO. Overexpression of glyoxalase I in HRP protected against S-p-bromobenzylglutathione cyclopentyl diester-induced apoptosis under high glucose conditions. Incubation of HRP with high concentrations of MGO resulted in an increase of apoptosis relative to untreated controls. We found an elevation of nitric oxide (NO·) in HRP that was incubated with high glucose when compared with those incubated with either the L-glucose or untreated controls. When HRP were incubated with an NO· donor, DETANONOATE ((Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate), we observed both decreased glyoxalase I expression and activity relative to untreated control cells. Further studies showed that HRP underwent apoptosis when incubated with DETANONOATE and that apoptosis increased further on co-incubation with high glucose. Our findings indicate that glyoxalase I is critical for pericyte survival under hyperglycemic conditions, and its inactivation and/or down-regulation by NO· may contribute to pericyte death by apoptosis during the early stages of diabetic retinopathy.

Received for publication, December 27, 2005 , and in revised form, February 21, 2006.

^* This work was supported by National Institutes of Health Grants R01EY-09912, R01EY-016219, and R21DK-068045 (to R. H. N.) and P30EY-11373 (to the Visual Sciences Research Center, Case Western Reserve University) and grants from Research to Prevent Blindness and the Ohio Lions Eye Research Foundation. 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.

¹ To whom correspondence should be addressed: Dept. of Ophthalmology, Wearn Bldg., Rm. 653, Case Western Reserve University, Cleveland, OH 44106. Tel.: 216-844-1132; Fax: 216-844-7962; E-mail: ram.nagaraj{at}case.edu.

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