Soluble and membrane-bound adenylate kinase and nucleotidases augment ATP-mediated inflammation in diabetic retinopathy eyes with vitreous hemorrhage

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Zeiner , J , Loukovaara , S , Losenkova , K , Zuccarini , M , Korhonen , A M , Lehti , K , Kauppinen , A , Kaarniranta , K , Mueller , C E , Jalkanen , S & Yegutkin , G G 2019 , ' Soluble and membrane-bound adenylate kinase and nucleotidases augment ATP-mediated inflammation in diabetic retinopathy eyes with vitreous hemorrhage ' , Journal of Molecular Medicine , vol. 97 , no. 3 , pp. 341-354 . https://doi.org/10.1007/s00109-018-01734-0

Title: Soluble and membrane-bound adenylate kinase and nucleotidases augment ATP-mediated inflammation in diabetic retinopathy eyes with vitreous hemorrhage
Author: Zeiner, Julian; Loukovaara, Sirpa; Losenkova, Karolina; Zuccarini, Mariachiara; Korhonen, Ani M.; Lehti, Kaisa; Kauppinen, Anu; Kaarniranta, Kai; Mueller, Christa E.; Jalkanen, Sirpa; Yegutkin, Gennady G.
Contributor: University of Helsinki, Department of Ophthalmology and Otorhinolaryngology
University of Helsinki, Research Programs Unit
University of Helsinki, Kaisa Irene Lehti / Principal Investigator
Date: 2019-03
Language: eng
Number of pages: 14
Belongs to series: Journal of Molecular Medicine
ISSN: 0946-2716
URI: http://hdl.handle.net/10138/299970
Abstract: ATP and adenosine are important signaling molecules involved in vascular remodeling, retinal function, and neurovascular coupling in the eye. Current knowledge on enzymatic pathways governing the duration and magnitude of ocular purinergic signaling is incompletely understood. By employing sensitive analytical assays, this study dissected ocular purine homeostasis as a complex and coordinated network. Along with previously characterized ecto-5-nucleotidase/CD73 and adenylate kinase activities, other enzymes have been identified in vitreous fluids, including nucleoside triphosphate diphosphohydrolase (NTPDase), adenosine deaminase, and alkaline phosphatase. Strikingly, activities of soluble adenylate kinase, adenosine deaminase, ecto-5-nucleotidase/CD73, and alkaline phosphatase, as well as intravitreal concentrations of ATP and ADP, were concurrently upregulated in patients suffering from diabetic retinopathy (DR) with non-clearing vitreous hemorrhage (VH), when compared to DR eyes without VH and control eyes operated due to macular hole or pucker. Additional histochemical analysis revealed selective distribution of key ecto-nucleotidases (NTPDase1/CD39, NTPDase2, ecto-5-nucleotidase/CD73, and alkaline phosphatase) in the human sensory neuroretina and optic nerve head, and also in pathological neofibrovascular tissues surgically excised from patients with advanced proliferative DR. Collectively, these data provide evidence for specific hemorrhage-related shifts in purine homeostasis in DR eyes from the generation of anti-inflammatory adenosine towards a pro-inflammatory and pro-angiogenic ATP-regenerating phenotype. In the future, identifying the exact mechanisms by which a broad spectrum of soluble and membrane-bound enzymes coordinately regulates ocular purine levels and the further translation of purine-converting enzymes as potential therapeutic targets in the treatment of proliferative DR and other vitreoretinal diseases will be an area of intense interest.Key messagesNTPDase, alkaline phosphatase, and adenosine deaminase circulate in human vitreous.Purinergic enzymes are up-regulated in diabetic eyes with vitreous hemorrhage.Soluble adenylate kinase maintains high ATP levels in diabetic retinopathy eyes.Ecto-nucleotidases are co-expressed in the human retina and optic nerve head.Alkaline phosphatase is expressed on neovascular tissues excised from diabetic eyes.
Subject: Diabetic vitreous hemorrhage
Intravitreal ATP
Retina
Optic nerve head
Soluble adenylate kinase
Alkaline phosphatase
Ecto-nucleotidases
EXTRACELLULAR ATP
ADENOSINE
RECEPTORS
MOUSE
BLOOD
ECTONUCLEOTIDASES
METABOLISM
GLAUCOMA
PURINES
TARGETS
3111 Biomedicine
1184 Genetics, developmental biology, physiology
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