June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
Overactive Arginase Causes Mitochondrial Dysfunction and Premature Endothelial Cell Senescence during Diabetic Retinopathy
Author Affiliations & Notes
  • Ruth Caldwell
    Vascular Biology Center, Georgia Health Sciences University, Augusta, GA
    Charlie Norwood VA Medical Center, Augusta, GA
  • S.Priya Narayanan
    Vascular Biology Center, Georgia Health Sciences University, Augusta, GA
  • Modesto Rojas
    Vascular Biology Center, Georgia Health Sciences University, Augusta, GA
  • Tahira Lemtalsi
    Vascular Biology Center, Georgia Health Sciences University, Augusta, GA
  • Zhimin Xu
    Vascular Biology Center, Georgia Health Sciences University, Augusta, GA
  • Kanjana Jittiporn
    Vascular Biology Center, Georgia Health Sciences University, Augusta, GA
  • Erica Schenhals
    Vascular Biology Center, Georgia Health Sciences University, Augusta, GA
  • Robert Caldwell
    Department of Pharmacology & Toxicology, Georgia Health Sciences University, Augusta, GA
  • David Fulton
    Vascular Biology Center, Georgia Health Sciences University, Augusta, GA
    Department of Pharmacology & Toxicology, Georgia Health Sciences University, Augusta, GA
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 4597. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Ruth Caldwell, S.Priya Narayanan, Modesto Rojas, Tahira Lemtalsi, Zhimin Xu, Kanjana Jittiporn, Erica Schenhals, Robert Caldwell, David Fulton, Vision Discovery Institute; Overactive Arginase Causes Mitochondrial Dysfunction and Premature Endothelial Cell Senescence during Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4597.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose: Our previous studies have shown that diabetes-induced vascular inflammation and impairment of endothelial-dependent vasorelaxation involve activation of the urea/ornithine producing enzyme arginase. Overactive arginase uncouples endothelial nitric oxide synthase (NOS), leading to increases in oxidative stress and decreases in NO bioavailability. These alterations have been linked to vascular injury and defective vascular repair during peripheral vascular disease by a mechanism involving stress-induced premature senescence of vascular endothelial cells (EC). Accelerated aging and premature senescence have been reported in diabetic patients at risk for developing peripheral vascular complications. However, EC senescence has not been addressed in diabetic retinopathy. Here we examined the potential role of overactive arginase in causing premature EC senescence and death during diabetic retinopathy.

Methods: Studies were performed in diabetic mice and high glucose-treated retinal vascular ECs treated with or without a specific arginase inhibitor. Mitochondrial dysfunction was determined by Mitosox Red imaging. Premature EC senescence was evaluated by assessing activity of the senescence marker SA β-galactosidase and Western blotting for the cell cycle negative regulator p16INK4a and putative upstream mediators of premature senescence [phosphorylation/activation of apoptosis signaling kinase 1 (p-ASK1), p-p38 MAPK and p-JNK]. Cell death was determined by TUNEL assay.

Results: Our studies showed that increased arginase expression and activity in diabetic retinas, hyperglycemia-treated retinal ECs or retinal ECs transduced with arginase I are associated with decreased NO formation, mitochondrial dysfunction, premature EC senescence and increased EC death. Blockade of arginase limited these effects.

Conclusions: This study shows for the first time that diabetes/high glucose induced injury and impaired survival of vascular ECs is mediated by a mechanism of premature EC senescence. Furthermore our results suggest that excessive arginase activity contributes to EC dysfunction and injury by reducing NO, increasing oxidative stress and causing mitochondrial dysfunction, resulting in premature EC senescence.

Keywords: 499 diabetic retinopathy • 634 oxidation/oxidative or free radical damage • 449 cell survival  
×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×