Document Detail

Poly-ADP-ribose-polymerase inhibition ameliorates hind limb ischemia reperfusion injury in a murine model of type 2 diabetes.
MedLine Citation:
PMID:  23549425     Owner:  NLM     Status:  MEDLINE    
INTRODUCTION: Diabetes is known to increase poly-ADP-ribose-polymerase (PARP) activity and posttranslational poly-ADP-ribosylation of several regulatory proteins involved in inflammation and energy metabolism. These experiments test the hypothesis that PARP inhibition will modulate hind limb ischemia reperfusion (IR) in a mouse model of type-II diabetes and ameliorate the ribosylation and the activity/transnuclear localization of the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH).
METHODS: db/db mice underwent 1.5 hours of hind limb ischemia followed by 1, 7, or 24 hours of reperfusion. The treatment group received the PARP inhibitor PJ34 (PJ34) over a 24-hour period; the untreated group received Lactated Ringer (LR) at the same time points. IR muscles were analyzed for indices of PARP activity, fiber injury, metabolic activity, inflammation, GAPDH activity/intracellular localization, and poly-ADP-ribosylation of GAPDH.
RESULTS: PARP activity was significantly lower in the PJ34-treated groups than in the Lactated Ringer group at 7 and 24 hours of reperfusion. There was significantly less muscle fiber injury in the PJ34-treated group than in the Lactated Ringer-treated mice at 24 hours of reperfusion. PJ34 lowered levels of select proinflammatory molecules at 7 hours and 24 hours of IR. There were significant increases in metabolic activity only at 24 hours of IR in the PJ34 group, which temporally correlated with increase in GAPDH activity, decreased GAPDH poly-ADP-ribosylation, and nuclear translocation of GAPDH.
CONCLUSIONS: PJ34 reduced PARP activity, GAPDH ribosylation, and GAPDH translocation; ameliorated muscle fiber injury; and increased metabolic activity after hind limb IR injury in a murine model of type-II diabetes. PARP inhibition might be a therapeutic strategy after IR in diabetic humans.
Chandler A Long; Valy Boulom; Hassan Albadawi; Shirling Tsai; Hyung-Jin Yoo; Rahmi Oklu; Mitchell H Goldman; Michael T Watkins
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Annals of surgery     Volume:  258     ISSN:  1528-1140     ISO Abbreviation:  Ann. Surg.     Publication Date:  2013 Dec 
Date Detail:
Created Date:  2013-11-13     Completed Date:  2014-01-13     Revised Date:  2014-03-10    
Medline Journal Info:
Nlm Unique ID:  0372354     Medline TA:  Ann Surg     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1087-95     Citation Subset:  AIM; IM    
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MeSH Terms
Diabetes Mellitus, Type 2 / enzymology*
Disease Models, Animal
Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+) / physiology
Hindlimb / blood supply*
Poly(ADP-ribose) Polymerases / antagonists & inhibitors*
Reperfusion Injury / prevention & control*
Grant Support
Reg. No./Substance:
EC 3-Phosphate Dehydrogenase (NADP+); EC Polymerases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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