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Yagna P. R. Jarajapu, Sergio Caballero, Amrisha Verma, Takahiko Nakagawa, Margaret C. Lo, Qiuhong Li, Maria B. Grant; Blockade of NADPH Oxidase Restores Vasoreparative Function in Diabetic CD34+ Cells. Invest. Ophthalmol. Vis. Sci. 2011;52(8):5093-5104. doi: 10.1167/iovs.10-70911.
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© 2017 Association for Research in Vision and Ophthalmology.
The vasodegenerative phase of diabetic retinopathy is likely caused by endothelial dysfunction and reduced endothelial repair. Migration of endothelial progenitor cells (EPCs) into areas of vascular injury is critical to vascular repair. This key function, often defective in diabetes, is largely mediated by nitric oxide (NO), which is known to be inactivated by superoxide produced by NADPH oxidase. The authors tested the hypothesis that either increasing eNOS expression or inhibiting NADPH oxidase would restore the reparative function in diabetic EPCs.
Peripheral blood was obtained from healthy (n = 27) and diabetic (n = 31) persons, and CD34+ cells were isolated. Expression and activation of eNOS and NADPH oxidase and intracellular levels of NO, superoxide, and peroxynitrite were evaluated. cGMP production and migration to SDF-1α were also determined. Reparative function was evaluated in a mouse model of retinal ischemia-reperfusion injury.
Diabetic EPCs demonstrate reduced eNOS expression and decreased NO bioavailability and migration in response to SDF-1α. Increasing eNOS expression in diabetic cells by AVE3085 resulted in increased peroxynitrite levels and, therefore, did not enhance NO-mediated functions in vitro and in vivo. Expression of Nox2, NADPH oxidase activity, and superoxide levels were higher in diabetic than in nondiabetic EPCs. Pretreatment with apocynin or gp91ds-tat increased NO bioavailability without increasing eNOS activity in response to SDF-1α. Ex vivo NADPH oxidase inhibition in diabetic cells restored migratory function in vitro and enhanced their homing to ischemic retinal vasculature in vivo.
The NADPH oxidase system is a promising target for correcting vasoreparative dysfunction in diabetic EPCs.
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