title: Activation of poly(ADP-ribose) polymerase by myocardial ischemia and coronary reperfusion in human circulating leukocytes.
abstract: Reactive free radical and oxidant production leads to DNA damage during myocardial ischemia/reperfusion. Consequent overactivation of poly(ADP-ribose) polymerase (PARP) promotes cellular energy deficit and necrosis. We hypothesized that PARP is activated in circulating leukocytes in patients with myocardial infarction and reperfusion during primary percutaneous coronary intervention (PCI). In 15 patients with ST segment elevation acute myocardial infarction, before and after primary PCI and 24 and 96 h later, we determined serum hydrogen peroxide concentrations, plasma levels of the oxidative DNA adduct 8-hydroxy-2'-deoxyguanosine (8OHdG), tyrosine nitration, PARP activation, and translocation of apoptosis-inducing factor (AIF) in circulating leukocytes. Plasma 8OHdG levels and leukocyte tyrosine nitration were rapidly increased by PCI. Similarly, poly(ADP-ribose) content of the leukocytes increased in cells isolated just after PCI, indicating immediate PARP activation triggered by reperfusion of the myocardium. In contrast, serum hydrogen peroxide concentrations and the translocation of AIF gradually increased over time and were most pronounced at 96 h. Reperfusion-related oxidative/nitrosative stress triggers DNA damage, which leads to PARP activation in circulating leukocytes. Translocation of AIF and lipid peroxidation occurs at a later stage. These results represent the first direct demonstration of PARP activation in human myocardial infarction. Future work is required to test whether pharmacological inhibition of PARP may offer myocardial protection during primary PCI.
authors.affiliation: Cardiovascular Research Group of the Hungarian Academy of Sciences and Semmelweis University & National Health Center, Budapest, Hungary.
authors.forename: Emese
authors.initials: E
authors.lastname: Tóth-Zsámboki
authors.forename: Eszter
authors.initials: E
authors.lastname: Horváth
authors.forename: Katarina
authors.initials: K
authors.lastname: Vargova
authors.forename: Eszter
authors.initials: E
authors.lastname: Pankotai
authors.forename: Kanneganti
authors.initials: K
authors.lastname: Murthy
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Zsengellér
authors.forename: Tamás
authors.initials: T
authors.lastname: Bárány
authors.forename: Tamás
authors.initials: T
authors.lastname: Pék
authors.forename: Katalin
authors.initials: K
authors.lastname: Fekete
authors.forename: Róbert Gábor
authors.initials: RG
authors.lastname: Kiss
authors.forename: István
authors.initials: I
authors.lastname: Préda
authors.forename: Zsombor
authors.initials: Z
authors.lastname: Lacza
authors.forename: Domokos
authors.initials: D
authors.lastname: Gerö
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabó
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000368:Aged; D000787:Angina Pectoris / Q000201:enzymology / Q000473:pathology; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D004249:DNA Damage; D003710:Demography; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000097:blood; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007962:Leukocytes / Q000201:enzymology* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000201:enzymology* / Q000473:pathology; D015425:Myocardial Reperfusion / Q000379:methods*; D010084:Oxidation-Reduction; D010545:Peroxides / Q000097:blood; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D021381:Protein Transport; D014443:Tyrosine / Q000031:analogs & derivatives / Q000096:biosynthesis
chemical_list: D051033:Apoptosis Inducing Factor; D010545:Peroxides; C002744:3-nitrotyrosine; D014443:Tyrosine; D000080242:8-Hydroxy-2'-Deoxyguanosine; D011065:Poly(ADP-ribose) Polymerases; D003849:Deoxyguanosine