April 2014
Volume 55, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2014
Mechanistic role of arginase in inducing endothelial cell senescence in diabetic retinopathy
Author Affiliations & Notes
  • Esraa Shosha
    Vascular Biology Center, Georgia Regents University, Augusta, GA
  • Tahira Lemtalsi
    Vascular Biology Center, Georgia Regents University, Augusta, GA
  • Zhimin Xu
    Vascular Biology Center, Georgia Regents University, Augusta, GA
  • Robert William Caldwell
    Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, GA
  • Ruth B Caldwell
    Vascular Biology Center, Georgia Regents University, Augusta, GA
    VA Medical Center, Augusta, GA
  • S. Priya Narayanan
    Vascular Biology Center, Georgia Regents University, Augusta, GA
  • Footnotes
    Commercial Relationships Esraa Shosha, None; Tahira Lemtalsi, None; Zhimin Xu, None; Robert William Caldwell, None; Ruth Caldwell, None; S. Priya Narayanan, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 3557. doi:https://doi.org/
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      Esraa Shosha, Tahira Lemtalsi, Zhimin Xu, Robert William Caldwell, Ruth B Caldwell, S. Priya Narayanan; Mechanistic role of arginase in inducing endothelial cell senescence in diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3557. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: Previous studies from our laboratory have shown that diabetes-induced vascular inflammation and impairment of endothelial-dependent vasorelaxation involve activation of the urea/ornithine producing enzyme arginase. Recently, senescence in endothelial cells has been considered as a cause of diabetes related complications. We have shown that high glucose (HG) accelerates retinal endothelial cell senescence and inhibiting arginase activity blocks this effect. The present study investigated the potential involvement of a novel cellular senescence marker DEC1 (differentiated embryo-chondrocyte expressed gene 1), a target of the p53 family, the basic helix-loop-helix transcription factor, and an upstream mediator, c-Jun NH2-terminal kinase (JNK), in this process.

Methods: Studies were performed using diabetic mice [Ins2 (Akita) and streptozotocin (STZ)-diabetic], mice lacking one copy of arginase 1 (A1 KO) and bovine retinal endothelial (BRE) cells treated with high glucose. Protein extracts from BRE cells and fresh frozen retinas were collected for Western blotting. RT-PCR was performed using RNA isolated from fresh frozen retinal samples and isolated retinal vessels. Retinal sections and fixed cells were evaluated for senescence associated β-galactosidase activity assay. TUNEL assay was used to determine cell death.

Results: Our studies showed that arginase expression/activity, cellular senescence and cell death were increased in HG-treated BRE cells as well as in diabetic retinas. These changes were associated with activation of JNK in both HG treated BRE cells and diabetic retinas. The JNK activation was significantly reduced by inhibiting arginase activity with the pharmacological inhibitor ABH (amino-2-borono-6-hexanoic acid) in BRE cells or by A1 KO in mice. RT-PCR and Western blot analysis showed that the diabetes-induced activation of JNK was associated with increased expression of DEC1.

Conclusions: This study shows for the first time that diabetes/high glucose can induce vascular injury through arginase activation resulting in cellular senescence and cell death through a pathway involving JNK activation and upregulation of DEC1 expression. Our data suggests that diabetes and hyperglycemia induce retinal endothelial cell senescence and death by a mechanism involving arginase-induced cell stress and DEC1 activation. Inhibiting arginase can block this vascular injury.

Keywords: 499 diabetic retinopathy • 688 retina • 426 apoptosis/cell death  
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