4.7 Article

Hypoglycemia Induces Mitochondrial Reactive Oxygen Species Production Through Increased Fatty Acid Oxidation and Promotes Retinal Vascular Permeability in Diabetic Mice

Journal

ANTIOXIDANTS & REDOX SIGNALING
Volume 34, Issue 16, Pages 1245-1259

Publisher

MARY ANN LIEBERT, INC
DOI: 10.1089/ars.2019.8008

Keywords

diabetic retinopathy; fatty acid oxidation; hypoglycemia; manganese superoxide dismutase; mitochondrial reactive oxygen species; retinal vascular permeability

Funding

  1. Japan Society for the Promotion of Science [18K15422, 15K09393]
  2. Grants-in-Aid for Scientific Research [18K15422, 15K09393] Funding Source: KAKEN

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Hypoglycemia induces mitochondrial ROS production through fatty acid oxidation and leads to increased vascular permeability in retinal endothelial cells. Blocking fatty acid oxidation reduces mtROS production and prevents hypoglycemia-induced vascular permeability in the retina.
Aims:Hypoglycemia is associated with increased reactive oxygen species (ROS) production and vascular events. We have previously reported that low-glucose (LG) conditions induce mitochondrial ROS (mtROS) production in aortic endothelial cells (ECs). However, the mechanism by which hypoglycemia promotes diabetic retinopathy (DR) is unclear. Blood-retinal barrier (BRB) disruption occurs in the early stages of DR. We hypothesized that the mechanisms underlying hypoglycemia-induced DR are associated with BRB breakdown due to mtROS generation during hypoglycemia. Here, we aimed to determine whether hypoglycemia exacerbated mtROS production and induced BRB disruption. Results:We observed that hypoglycemia induced mtROS production by increasing fatty acid oxidation (FAO), which was suppressed by overexpression of mitochondrial-specific manganese superoxide dismutase (MnSOD) in retinal ECs. Furthermore, FAO blockade decreased the hypoglycemia-induced mtROS production. Recurrent hypoglycemia increased albumin leak in diabetic mice retina, which was suppressed in diabetic vascular endothelial cell-specific MnSOD transgenic (eMnSOD-Tg) mice. Pharmacological FAO blockade also reduced mtROS production, reduced vascular endothelial growth factor (VEGF) production during hypoglycemia, and prevented retinal vascular permeability in diabetic mice. MnSOD overexpression or carnitine palmitoyltransferase I (CPT1) blockade suppressed vascular endothelial-cadherin phosphorylation under LG in retinal ECs. Innovation and Conclusion:Reduction of mtROS and VEGF productionviapharmacological FAO and/or CPT1 blockade may prevent hypoglycemia-induced worsening of DR.

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