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Polyadenosine Diphosphate–Ribose Polymerase Inhibition Modulates Skeletal Muscle Injury Following Ischemia Reperfusion
Hong T. Hua, MD;
Hassan Albadawi, MD;
Fateh Entabi, MD;
Mark Conrad, MD;
Michael C. Stoner, MD;
Bryan T. Meriam, AB;
Ramses Sroufe, AB;
Stuart Houser, MD;
Glenn M. LaMuraglia, MD;
Michael T. Watkins, MD
Arch Surg. 2005;140:344-351.
Hypothesis Polyadenosine diphosphate–ribose polymerase (PARP) has been implicated as a mediator of inflammation and tissue necrosis in murine models of human stroke and myocardial infarction. This study was designed to determine whether PARP modulates skeletal muscle injury and cytokine-growth factor levels during ischemia-reperfusion.
Design Prospective controlled animal study.
Setting Medical school–affiliated university hospital.
Interventions Mice were divided into 2 groups—treated (PJ) and untreated; all mice were subjected to unilateral hind limb tourniquet ischemia followed by 4 or 48 hours of reperfusion. In treated mice, PJ34, an ultrapotent-specific PARP inhibitor was given immediately before ischemia and prior to reperfusion. A group of PARP-1 knockout mice (PARP–/–) were also subjected to hind limb ischemia followed by 48 hours of reperfusion.
Main Outcome Measures After ischemia-reperfusion, muscle was harvested for measurement of edema, viability, cytokine, and vascular endothelial growth factor content.
Results The PJ34-treated mice had increased skeletal muscle viability when compared with the untreated mice after 4 and 48 hours of reperfusion (P<.01). Viability between PARP–/– and PJ34-treated mice were similar at 48 hours of reperfusion (P>.05), and it exceeded that of untreated mice (P<.01). Tissue edema was unaltered by PARP inhibition. Tissue levels of cytokine were only different (P<.05) in PJ34-treated vs untreated mice at 48 hours of reperfusion. Vascular endothelial growth factor levels in PJ34-treated mice were markedly reduced when compared with untreated mice only after 4 hours of reperfusion (P<.01), and in PARP–/– mice (P<.01) at 48 hours of reperfusion.
Conclusions Polyadenosine diphosphate–ribose polymerase modulates skeletal muscle viability, cytokine and vascular endothelial growth factor synthesis during reperfusion. Polyadenosine diphosphate–ribose polymerase inhibition may represent a novel method to modulate skeletal muscle ischemia-reperfusion injury.
Author Affiliations: Division of Vascular and Endovascular Surgery (Drs Hua, Albadawi, Entabi, Conrad, Stoner, LaMuraglia, and Watkins and Messrs Meriam and Sroufe) and the Department of Pathology (Dr Houser), Massachusetts General Hospital, Harvard Medical School, and the Veterans Administration Boston Healthcare System (Dr Watkins), Boston.
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Polyadenosine Diphosphate–Ribose Polymerase Inhibition Modulates Skeletal Muscle Injury Following Ischemia Reperfusion—Invited Critique
Alden H. Harken
Arch Surg. 2005;140(4):352.
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