期刊
CELL DEATH AND DIFFERENTIATION
卷 18, 期 10, 页码 1651-1663出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2011.80
关键词
I/R injury; zinc; TPEN; flavonoids; GSK-3 beta; Noxa
资金
- National Science Council of Taiwan [NSC-98-2320-B-002-042-MY3, NSC 99-2314-B-166-001-MY3]
Oxidative stress and nitrosative stress are both suggested to be involved in cardiac ischemia-reperfusion (I/R) injury. Using time-lapse confocal microscopy of cardiomyocytes and high-affinity O(2)(-center dot) K and Zn(2+) probes, this study is the first to show that I/R, reactive oxygen species (ROS), and reactive nitrogen species (RNS) all cause a marked increase in the [O(2)(-center dot) K](i), resulting in cytosolic and mitochondrial Zn(2+) release. Exposure to a cell-penetrating, high-affinity Zn(i)(2+) chelator, TPEN, largely abolished the Zn(i)(2+) release and markedly protected myocytes from I/R-, ROS-, RNS-, or Zn(2+)/K(+) (Zn(i)(2+) supplementation)-induced myocyte apoptosis for at least 24 h after TPEN removal. Flavonoids and U0126 (a MEK1/2 inhibitor) largely inhibited the myocyte apoptosis and the TPEN-sensitive I/R- or Zn(i)(2+) supplement-induced persistent extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation, dephosphorylation of p-Ser9 on glycogen synthase kinase 3 beta (GSK-3 beta), and the translocation into and accumulation of p-Tyr216 GSK-3 beta and p53 in, the nucleus. Silencing of GSK-3 beta or p53 expression was cardioprotective, indicating that activation of the ERK-GSK-3 beta-p53 signaling pathway is involved in Zn(2+)-sensitive myocyte death. Moreover, the ERK-dependent Noxa-myeloid cell leukemia-1 (Mcl-1) pathway is also involved, as silencing of Noxa expression was cardioprotective and U0126 abolished both the increase in Noxa expression and in Mcl-1 degradation. Thus, acute upstream Zn(i)(2+) chelation at the start of reperfusion and the use of natural products, that is, flavonoids, may be beneficial in the treatment of cardiac I/R injury. Cell Death and Differentiation (2011) 18, 1651-1663; doi:10.1038/cdd.2011.80; published online 10 June 2011
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