title: Treatment with polyamine oxidase inhibitor reduces microglial activation and limits vascular injury in ischemic retinopathy.
abstract: Retinal vascular injury is a major cause of vision impairment in ischemic retinopathies. Insults such as hyperoxia, oxidative stress and inflammation contribute to this pathology. Previously, we showed that hyperoxia-induced retinal neurodegeneration is associated with increased polyamine oxidation. Here, we are studying the involvement of polyamine oxidases in hyperoxia-induced injury and death of retinal vascular endothelial cells. New-born C57BL6/J mice were exposed to hyperoxia (70% O2) from postnatal day (P) 7 to 12 and were treated with the polyamine oxidase inhibitor MDL 72527 or vehicle starting at P6. Mice were sacrificed after different durations of hyperoxia and their retinas were analyzed to determine the effects on vascular injury, microglial cell activation, and inflammatory cytokine profiling. The results of this analysis showed that MDL 72527 treatment significantly reduced hyperoxia-induced retinal vascular injury and enhanced vascular sprouting as compared with the vehicle controls. These protective effects were correlated with significant decreases in microglial activation as well as levels of inflammatory cytokines and chemokines. In order to model the effects of polyamine oxidation in causing microglial activation in vitro, studies were performed using rat brain microvascular endothelial cells treated with conditioned-medium from rat retinal microglia stimulated with hydrogen peroxide. Conditioned-medium from activated microglial cultures induced cell stress signals and cell death in microvascular endothelial cells. These studies demonstrate the involvement of polyamine oxidases in hyperoxia-induced retinal vascular injury and retinal inflammation in ischemic retinopathy, through mechanisms involving cross-talk between endothelial cells and resident retinal microglia.
authors.affiliation: Vision Discovery Institute, Augusta University, Augusta, GA 30912, USA; Vascular Biology Center, Augusta University, Augusta, GA 30912, USA; Department of Occupational Therapy, College of Allied Health Sciences, Augusta University, Augusta, GA 30912, USA. Electronic address: cpatel1@augusta.edu.
authors.forename: C
authors.initials: C
authors.lastname: Patel
authors.affiliation: Vision Discovery Institute, Augusta University, Augusta, GA 30912, USA; Vascular Biology Center, Augusta University, Augusta, GA 30912, USA. Electronic address: zhxu@augusta.edu.
authors.forename: Z
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Vision Discovery Institute, Augusta University, Augusta, GA 30912, USA; Vascular Biology Center, Augusta University, Augusta, GA 30912, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA. Electronic address: eshosha@augusta.edu.
authors.forename: E
authors.initials: E
authors.lastname: Shosha
authors.affiliation: Vision Discovery Institute, Augusta University, Augusta, GA 30912, USA; Vascular Biology Center, Augusta University, Augusta, GA 30912, USA. Electronic address: jxing8733@163.com.
authors.forename: J
authors.initials: J
authors.lastname: Xing
authors.affiliation: Vascular Biology Center, Augusta University, Augusta, GA 30912, USA; Department of Pharmacology & Toxicology, Augusta University, Augusta, GA 30912, USA. Electronic address: rlucas@augusta.edu.
authors.forename: R
authors.initials: R
authors.lastname: Lucas
authors.affiliation: Department of Pharmacology & Toxicology, Augusta University, Augusta, GA 30912, USA. Electronic address: wcaldwel@augusta.edu.
authors.forename: R W
authors.initials: RW
authors.lastname: Caldwell
authors.affiliation: Vision Discovery Institute, Augusta University, Augusta, GA 30912, USA; Vascular Biology Center, Augusta University, Augusta, GA 30912, USA; Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA 30912, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA. Electronic address: rcaldwel@augusta.edu.
authors.forename: R B
authors.initials: RB
authors.lastname: Caldwell
authors.affiliation: Vision Discovery Institute, Augusta University, Augusta, GA 30912, USA; Vascular Biology Center, Augusta University, Augusta, GA 30912, USA; Department of Occupational Therapy, College of Allied Health Sciences, Augusta University, Augusta, GA 30912, USA. Electronic address: pnarayanan@augusta.edu.
authors.forename: S P
authors.initials: SP
authors.lastname: Narayanan
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007511:Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors*; D011700:Putrescine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D012164:Retinal Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012171:Retinal Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000097667:Polyamine Oxidase
chemical_list: D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D000587:Oxidoreductases Acting on CH-NH Group Donors; D011700:Putrescine; D000097667:Polyamine Oxidase; C044445:MDL 72527