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NORMALIZING DYSFUNCTIONAL PURINE METABOLISM IN THE DIABETIC REGENERATIVE ENVIRONMENT ACCELERATES CUTANEOUS WOUND HEALING
Presenter: Frank Lalezarzadeh, BS
Co-Authors: Wilson SC; Weinsten AL; Soares MA; Ham MJ; Lotfi P; Ojo CO; Sartor RA; Saadeh PB; Ceradini DJ
New York University

Introduction: Dysregulation in purine metabolism is strongly implicated in diabetic complications. Purine metabolism is dependent on xanthine dehydrogenase (XDH), which under stress is converted to xanthine oxidase (XO), and can generate reactive oxygen species (ROS). Therefore, we hypothesize that targeted inhibition of XDH will normalize purine metabolism in the diabetic regenerative environment, decrease ROS accumulation, and accelerate wound healing.

Methods: 3T3 fibroblasts cultured in hyper- and normoglycemic conditions were transfected with siXDH; the efficacy of our therapeutic strategy was determined through XDH RNA expression and XO protein functional activity. Using a validated stented wound healing model, topical XDH siRNA (siXDH) was applied to wild type (WT) and diabetic db/db mice (DB). Wound healing was characterized by XDH mRNA expression, XO protein functional activity, and end products of ROS (8-OHDG ELISA). Wound time to closure was histologically and photometrically assessed.

Results: In vitro, siXDH therapy effectively decreased both XDH mRNA expression (2.15-fold, p<.001) and subsequent functional activity (1.767 mU/mL vs. 1.325 mU/mL p<.01). In vivo, XO activity was significantly increased in DB wounds (21.73 mU/mL) vs. WT wounds (12.857 mU/mL) (p<.0001). This culminated to a significant 9.18-fold increase of ROS in DB wounds vs. WT wounds (p<.01). siXDH topical therapy significantly decreased XO functional activity in DB wounds vs. control (p<.01), with a subsequent significant decrease in ROS levels in treated DB mice (.854 ng/mL) vs. untreated DB mice (3.58 ng/mL) (p<.05). Topical siXDH therapy accelerated diabetic wound closure by greater than 4 days (20% increase in rate, p<.05) compared to control.

Summary: Alterations in purine metabolism significantly impairs wound healing in diabetics. Normalization of this overactive metabolic pathway in the regenerative niche through topically-delivered siXDH is clinically translatable and is a novel strategy for a significant clinical burden.


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