Polyadenosine Diphosphate–Ribose Polymerase Inhibition Modulates Skeletal Muscle Injury Following Ischemia Reperfusion

• Published in: Archives of surgery (Chicago. 1960) Vol. 140; no. 4; pp. 344 - 351
• Main Authors: Hua, Hong T, Albadawi, Hassan, Entabi, Fateh, Conrad, Mark, Stoner, Michael C, Meriam, Bryan T, Sroufe, Ramses, Houser, Stuart, LaMuraglia, Glenn M, Watkins, Michael T
• Format: Journal Article
• Language: English
• Published: United States American Medical Association 01.04.2005
• Subjects: Analysis of Variance; Animals; Chemokines, CXC - metabolism; Hindlimb; Immunoenzyme Techniques; Mice; Mice, Inbred Strains; Muscle, Skeletal - drug effects; Muscle, Skeletal - physiopathology; Phenanthrenes - pharmacology; Poly Adenosine Diphosphate Ribose - antagonists & inhibitors; Prospective Studies; Reperfusion Injury - prevention & control; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0004-0010; 1538-3644
• DOI: 10.1001/archsurg.140.4.344

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.Arch Surg. 2005;140:344-351-->