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Absence of poly(ADP-ribose)polymerase-1 alters nuclear factor-kappa B activation and gene expression of apoptosis regulators after reperfusion injury.

Abstract
Poly(ADP-ribose) polymerase-1 (PARP-1) is activated in response to DNA injury in eukaryotic cells and has been implicated in cell dysfunction in reperfusion injury. In this study we investigated the role of PARP-1 on apoptosis in early myocardial reperfusion injury. Mice genetically deficient of PARP-1 (PARP-1-/-) and wild-type littermates were subjected to myocardial ischemia and reperfusion. Myocardial injury was assessed by measuring the serum levels of creatine phosphokinase and oligonucleosomal DNA fragments in the infarcted area. Expression of the anti-apoptotic protein, Bcl-2, and the pro-apoptotic protein, Bax, was analyzed by Western blot. Activation of caspases, important executioners of apoptosis, and activation of the nuclear factor kappa B (NF-kappa B) pathway were evaluated. Gene expression profiles for apoptotic regulators between PARP-1-/- and wild-type mice also were compared. Myocardial damage in PARP-1-/- mice was reduced significantly, as indicated by lower serum creatine phosphokinase levels and reduction of apoptosis, as compared with wild-type mice. Western blot analyses showed increased expression of Bcl-2, which was associated with reduction of caspase-1 and caspase-3 activation. This cardioprotection was associated with significant reduction of the activation of I kappa B kinase complex and NF-kappa B DNA binding. Microarray analysis demonstrated that the expression of 29 known genes of apoptotic regulators was significantly altered in PARP-1-/- mice compared with wild-type mice, whereas 6 known genes were similarly expressed in both genotypes. The data indicate that during reperfusion absence of PARP-1 leads to reduction of myocardial apoptosis, which is associated with reduced NF-kappa B activation and altered gene expression profiles.
AuthorsBasilia Zingarelli, Paul W Hake, Michael O'Connor, Alvin Denenberg, Sue Kong, Bruce J Aronow
JournalMolecular medicine (Cambridge, Mass.) (Mol Med) 2003 May-Aug Vol. 9 Issue 5-8 Pg. 143-53 ISSN: 1076-1551 [Print] United States
PMID14571322 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • I-kappa B Proteins
  • NF-kappa B
  • Proto-Oncogene Proteins c-bcl-2
  • NF-kappaB inhibitor alpha
  • Poly(ADP-ribose) Polymerases
  • Chuk protein, mouse
  • Ikbke protein, mouse
  • Protein-Serine-Threonine Kinases
  • I-kappa B Kinase
  • Ikbkb protein, mouse
  • Casp3 protein, mouse
  • Caspase 3
  • Caspases
  • Caspase 1
Topics
  • Animals
  • Apoptosis (genetics, physiology)
  • Caspase 1 (metabolism)
  • Caspase 3
  • Caspases (metabolism)
  • I-kappa B Kinase
  • I-kappa B Proteins (metabolism)
  • Mice
  • Myocardial Ischemia (metabolism)
  • Myocardial Reperfusion
  • Myocardial Reperfusion Injury (metabolism)
  • Myocardium (metabolism)
  • NF-kappa B (metabolism)
  • Poly(ADP-ribose) Polymerases (deficiency, genetics, metabolism)
  • Protein-Serine-Threonine Kinases (metabolism)
  • Proto-Oncogene Proteins c-bcl-2 (metabolism)

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