title: Temporal dystrophic remodeling within the intrinsic cardiac nervous system of the streptozotocin-induced diabetic rat model.
abstract: BACKGROUND
  The pathogenesis of heart failure (HF) in diabetic individuals, called "diabetic cardiomyopathy", is only partially understood. Alterations in the cardiac autonomic nervous system due to oxidative stress have been implicated. The intrinsic cardiac nervous system (ICNS) is an important regulatory pathway of cardiac autonomic function, however, little is known about the alterations that occur in the ICNS in diabetes. We sought to characterize morphologic changes and the role of oxidative stress within the ICNS of diabetic hearts. Cultured ICNS neuronal cells from the hearts of 3- and 6-month old type 1 diabetic streptozotocin (STZ)-induced diabetic Sprague-Dawley rats and age-matched controls were examined. Confocal microscopy analysis for protein gene product 9.5 (PGP 9.5) and amino acid adducts of (E)-4-hydroxy-2-nonenal (4-HNE) using immunofluorescence was undertaken. Cell morphology was then analyzed in a blinded fashion for features of neuronal dystrophy and the presence of 4-HNE adducts.
  
  
  RESULTS
  At 3-months, diabetic ICNS neuronal cells exhibited 30% more neurite swellings per area (p = 0.01), and had a higher proportion with dystrophic appearance (88.1% vs. 50.5%; p = <0.0001), as compared to control neurons. At 6-months, diabetic ICNS neurons exhibited more features of dystrophy as compared to controls (74.3% vs. 62.2%; p = 0.0448), with 50% more neurite branching (p = 0.0015) and 50% less neurite outgrowth (p = <0.001). Analysis of 4-HNE adducts in ICNS neurons of 6-month diabetic rats demonstrated twice the amount of reactive oxygen species (ROS) as compared to controls (p = <0.001).
  
  
  CONCLUSIONS
  Neuronal dystrophy occurs in the ICNS neurons of STZ-induced diabetic rats, and accumulates temporally within the disease process. In addition, findings implicate an increase in ROS within the neuronal processes of ICNS neurons of diabetic rats suggesting an association between oxidative stress and the development of dystrophy in cardiac autonomic neurons.
authors.forename: Chantalle E
authors.initials: CE
authors.lastname: Menard
authors.forename: Melanie
authors.initials: M
authors.lastname: Durston
authors.forename: Elena
authors.initials: E
authors.lastname: Zherebitskaya
authors.forename: Darrell R
authors.initials: DR
authors.lastname: Smith
authors.forename: Darren
authors.initials: D
authors.lastname: Freed
authors.forename: Gordon W
authors.initials: GW
authors.lastname: Glazner
authors.forename: Ganghong
authors.initials: G
authors.lastname: Tian
authors.forename: Paul
authors.initials: P
authors.lastname: Fernyhough
authors.affiliation: University of Manitoba, Manitoba, Canada. rarora@sbgh.mb.ca.
authors.forename: Rakesh C
authors.initials: RC
authors.lastname: Arora
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D001341:Autonomic Nervous System / Q000503:physiopathology*; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000473:pathology*; D004195:Disease Models, Animal; D006331:Heart Diseases / Q000209:etiology* / Q000473:pathology; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D019150:Neuroaxonal Dystrophies / Q000209:etiology*; D009474:Neurons / Q000187:drug effects; D020933:Neurotrophin 3 / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043222:Ubiquitin Thiolesterase / Q000378:metabolism
chemical_list: D000447:Aldehydes; D015853:Cysteine Proteinase Inhibitors; D020933:Neurotrophin 3; C489034:UCHL1 protein, rat; D043222:Ubiquitin Thiolesterase; C027576:4-hydroxy-2-nonenal