Activation of poly(ADP-ribose) polymerase by myocardial ischemia and coronary reperfusion in human circulating leukocytes.
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.
Tóth-Zsámboki
Emese
E
Cardiovascular Research Group of the Hungarian Academy of Sciences and Semmelweis University & National Health Center, Budapest, Hungary.
Horváth
Eszter
E
Vargova
Katarina
K
Pankotai
Eszter
E
Murthy
Kanneganti
K
Zsengellér
Zsuzsanna
Z
Bárány
Tamás
T
Pék
Tamás
T
Fekete
Katalin
K
Kiss
Róbert Gábor
RG
Préda
István
I
Lacza
Zsombor
Z
Gerö
Domokos
D
Szabó
Csaba
C
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
D051033:Apoptosis Inducing Factor; D010545:Peroxides; C002744:3-nitrotyrosine; D014443:Tyrosine; D000080242:8-Hydroxy-2'-Deoxyguanosine; D011065:Poly(ADP-ribose) Polymerases; D003849:Deoxyguanosine