Endothelial arginase 2 mediates retinal ischemia/reperfusion injury by inducing mitochondrial dysfunction

Esraa Shosha; Abdelrahman Y. Fouda; Tahira Lemtalsi; Stephen Haigh; David Fulton; Ahmed Ibrahim; Mohamed Al-Shabrawey; R. William Caldwell; Ruth B. Caldwell

Molecular Metabolism (Nov 2021)

Endothelial arginase 2 mediates retinal ischemia/reperfusion injury by inducing mitochondrial dysfunction

Esraa Shosha,
Abdelrahman Y. Fouda,
Tahira Lemtalsi,
Stephen Haigh,
David Fulton,
Ahmed Ibrahim,
Mohamed Al-Shabrawey,
R. William Caldwell,
Ruth B. Caldwell

Affiliations

Esraa Shosha: Vascular Biology Center, Augusta University, Augusta, GA, USA; Department of Clinical Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt; Vision Discovery Institute, Augusta University, Augusta, GA, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA
Abdelrahman Y. Fouda: Vascular Biology Center, Augusta University, Augusta, GA, USA; Department of Clinical Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt; Vision Discovery Institute, Augusta University, Augusta, GA, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA
Tahira Lemtalsi: Vascular Biology Center, Augusta University, Augusta, GA, USA; Vision Discovery Institute, Augusta University, Augusta, GA, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA
Stephen Haigh: Vascular Biology Center, Augusta University, Augusta, GA, USA
David Fulton: Vascular Biology Center, Augusta University, Augusta, GA, USA
Ahmed Ibrahim: Vision Discovery Institute, Augusta University, Augusta, GA, USA; Wayne State University, Department of Ophthalmology, Visual, and Anatomical Sciences, Department of Pharmacology, Detroit, MI, USA; Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
Mohamed Al-Shabrawey: Vision Discovery Institute, Augusta University, Augusta, GA, USA; Department of Oral Biology, Dental College of Georgia, Augusta, GA, USA
R. William Caldwell: Vision Discovery Institute, Augusta University, Augusta, GA, USA; Department of Pharmacology and Toxicology, Augusta University, Augusta, GA, USA
Ruth B. Caldwell: Vascular Biology Center, Augusta University, Augusta, GA, USA; Vision Discovery Institute, Augusta University, Augusta, GA, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA; Corresponding author. Medical College of Georgia, Augusta University, 1460 Laney Walker Blvd, CB 3209A, Augusta, GA 30912, USA.

Journal volume & issue: Vol. 53
p. 101273

Abstract

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Objective: Retinal ischemic disease is a major cause of vision loss. Current treatment options are limited to late-stage diseases, and the molecular mechanisms of the initial insult are not fully understood. We have previously shown that the deletion of the mitochondrial arginase isoform, arginase 2 (A2), limits neurovascular injury in models of ischemic retinopathy. Here, we investigated the involvement of A2-mediated alterations in mitochondrial dynamics and function in the pathology. Methods: We used wild-type (WT), global A2 knockout (A2KO-) mice, cell-specific A2 knockout mice subjected to retinal ischemia/reperfusion (I/R), and bovine retinal endothelial cells (BRECs) subjected to an oxygen-glucose deprivation/reperfusion (OGD/R) insult. We used western blotting to measure levels of cell stress and death markers and the mitochondrial fragmentation protein, dynamin related protein 1 (Drp1). We also used live cell mitochondrial labeling and Seahorse XF analysis to evaluate mitochondrial fragmentation and function, respectively. Results: We found that the global deletion of A2 limited the I/R-induced disruption of retinal layers, fundus abnormalities, and albumin extravasation. The specific deletion of A2 in endothelial cells was protective against I/R-induced neurodegeneration. The OGD/R insult in BRECs increased A2 expression and induced cell stress and cell death, along with decreased mitochondrial respiration, increased Drp1 expression, and mitochondrial fragmentation. The overexpression of A2 in BREC also decreased mitochondrial respiration, promoted increases in the expression of Drp1, mitochondrial fragmentation, and cell stress and resulted in decreased cell survival. In contrast, the overexpression of the cytosolic isoform, arginase 1 (A1), did not affect these parameters. Conclusions: This study is the first to show that A2 in endothelial cells mediates retinal ischemic injury through a mechanism involving alterations in mitochondrial dynamics and function.

Published in Molecular Metabolism

ISSN: 2212-8778 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine
Website: https://www.journals.elsevier.com/molecular-metabolism/

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