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Poly-ADP-Ribose-Polymerase Inhibition Ameliorates Hind Limb Ischemia Reperfusion Injury in a Murine Model of Type 2 Diabetes

Long, Chandler A. MD*,†; Boulom, Valy MD*,‡; Albadawi, Hassan MD*; Tsai, Shirling MD*; Yoo, Hyung-Jin MD*; Oklu, Rahmi MD, PhD§; Goldman, Mitchell H. MD; Watkins, Michael T. MD, FACS, FAHA*,¶

doi: 10.1097/SLA.0b013e31828cced3
Original Articles

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.

Poly-ADP-ribose-polymerase (PARP) inhibition reduced PARP activity, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) ribosylation, and GAPDH translocation; ameliorated muscle fiber injury; and increased metabolic activity after hind limb ischemia reperfusion injury in a murine model of type-II diabetes. PARP inhibition might be a therapeutic strategy after ischemia reperfusion in diabetic humans.

*Division of Vascular and Endovascular Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, and The University of Tennessee Medical Center, Knoxville, TN

Department of Surgery, The University of Tennessee Graduate School of Medicine, Knoxville, TN

Department of Surgery, Sinai Hospital, Baltimore, MD

§Division of Vascular Imaging and Intervention, Massachusetts General Hospital, Harvard Medical School, Boston, MA, and The University of Tennessee Medical Center, Knoxville, TN; and

Division of Vascular and Endovascular Surgery, Massachusetts General Hospital, Boston, MA

Reprints: Michael T. Watkins, MD, FACS, FAHA, Division of Vascular and Endovascular Surgery, Massachusetts General Hospital, 15 Parkman Street, Suite 440, Boston, MA 02114. E-mail: mtwatkins@partners.org.

Drs. Chandler Long and Valy contributed equally as first authors to this work.

Disclosure: This study was funded by the National Institutes of Health (1R01AR055843); the American Diabetes Association; the Pacific Vascular Research Foundation, the Department of Surgery, Division of Vascular and Endovascular Surgery, Massachusetts General Hospital (The Geneen Fund); the Department of Surgery, The University of Tennessee, Knoxville; and Sinai Hospital, Baltimore, MD. The authors declare no conflicts of interest.

© 2013 by Lippincott Williams & Wilkins.