The critical role of intracellular zinc in adenosine A(2) receptor activation induced cardioprotection against reperfusion injury.
Exogenous zinc can protect cardiac cells from reperfusion injury, but the exact roles of endogenous zinc in the pathogenesis of reperfusion injury and in adenosine A(2) receptor activation-induced cardioprotection against reperfusion injury remain unknown. Adenosine A(1)/A(2) receptor agonist 5'-(N-ethylcarboxamido) adenosine (NECA) given at reperfusion reduced infarct size in isolated rat hearts subjected to 30min ischemia followed by 2h of reperfusion. This effect of NECA was partially but significantly blocked by the zinc chelator N,N,N',N'-tetrakis-(2-pyridylmethyl) ethylenediamine (TPEN), and ZnCl(2) given at reperfusion mimicked the effect of NECA by reducing infarct size. Total tissue zinc concentrations measured with inductively coupled plasma optical emission spectroscopy (ICPOES) were decreased upon reperfusion in rat hearts and this was reversed by NECA. NECA increased intracellular free zinc during reperfusion in the heart. Confocal imaging study showed a rapid increase in intracellular free zinc in isolated rat cardiomyocytes treated with NECA. Further experiments revealed that NECA increased total zinc levels upon reperfusion in mitochondria isolated from isolated hearts. NECA attenuated mitochondrial swelling upon reperfusion in isolated hearts and this was inhibited by TPEN. Similarly, NECA prevented the loss of mitochondrial membrane potential (DeltaPsim) caused by oxidant stress in cardiomyocytes. Finally, both NECA and ZnCl(2) inhibited the mitochondrial metabolic activity. NECA-induced cardioprotection against reperfusion injury is mediated by intracellular zinc. NECA prevents reperfusion-induced zinc loss and relocates zinc to mitochondria. The inhibitory effects of zinc on both the mPTP opening and the mitochondrial metabolic activity may account for the cardioprotective effect of NECA.
Department of Anesthesiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Rachel
R
McIntosh
Sungryul
S
Lee
Andrew J
AJ
Ghio
Jinkun
J
Xi
Min
M
Zhu
Xiangjun
X
Shen
Guillaume
G
Chanoit
David A
DA
Zvara
Zhelong
Z
Xu
D000241:Adenosine / Q000378:metabolism / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D003593:Cytoplasm / Q000378:metabolism; D005029:Ethylenediamines / Q000378:metabolism / Q000494:pharmacology; D006321:Heart; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D015032:Zinc / Q000378:metabolism* / Q000494:pharmacology*
D005029:Ethylenediamines; D019830:Adenosine-5'-(N-ethylcarboxamide); C031234:ethylenediamine; D015032:Zinc; D000241:Adenosine; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine