Polyadenosine diphosphate-ribose polymerase inhibition modulates skeletal muscle injury following ischemia reperfusion.

Abstract

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.

• Authors: Hong T Hua, Hassan Albadawi, Fateh Entabi, Mark Conrad, Michael C Stoner, Bryan T Meriam, Ramses Sroufe, Stuart Houser, Glenn M Lamuraglia, Michael T Watkins
• Journal: Archives of surgery (Chicago, Ill. : 1960) (Arch Surg) Vol. 140 Issue 4 Pg. 344-51; discussion 351-2 (Apr 2005) ISSN: 0004-0010 [Print] United States
• PMID: 15837884 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokines, CXC
• N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride
• Phenanthrenes
• Vascular Endothelial Growth Factor A
• Poly Adenosine Diphosphate Ribose

Topics

• Analysis of Variance
• Animals
• Chemokines, CXC (metabolism)
• Hindlimb
• Immunoenzyme Techniques
• Mice
• Mice, Inbred Strains
• Muscle, Skeletal (drug effects, physiopathology)
• Phenanthrenes (pharmacology)
• Poly Adenosine Diphosphate Ribose (antagonists & inhibitors)
• Prospective Studies
• Reperfusion Injury (prevention & control)
• Vascular Endothelial Growth Factor A (metabolism)