PMID- 22525374
OWN - NLM
STAT- MEDLINE
DCOM- 20121101
LR  - 20211021
IS  - 1879-0631 (Electronic)
IS  - 0024-3205 (Print)
IS  - 0024-3205 (Linking)
VI  - 91
IP  - 7-8
DP  - 2012 Sep 17
TI  - DNase activation by hypoxia-acidosis parallels but is independent of programmed 
      cell death.
PG  - 223-9
LID - 10.1016/j.lfs.2012.03.034 [doi]
AB  - AIMS: Hypoxia, acidosis and programmed cell death are each hallmarks of acute 
      myocardial infarction (AMI). We previously described a death pathway of cardiac 
      myocytes mediated by hypoxia-acidosis that was characterized by activation of the 
      Bcl2-family protein Bnip3 and programmed necrosis. The pathway included extensive 
      DNA fragmentation that was sensitive to inhibition of the mitochondrial 
      permeability transition pore (mPTP) and calpain inhibitors, but not caspase 
      inhibitors. We did not identify the DNases responsible for DNA cleavage. MAIN 
      METHODS: Neonatal rat cardiomyocytes were subjected to hypoxia with and without 
      concurrent acidosis, and the cellular localization of apoptosis-inducing factor 
      (AIF), DNase II and caspase-dependent DNase (CAD) were determined. KEY FINDINGS: 
      Here we report the occurrence of biphasic pH-dependent translocations of AIF and 
      DNase II but no change in CAD or its inhibitor ICAD. AIF co-localized with the 
      mitochondria under aerobic and hypoxia-neutral conditions but translocated to the 
      nucleus at pH ~6.7 coincident with a decrease of the mitochondrial membrane 
      potential. DNase II co-localized with lysosomes under normoxia and 
      hypoxia-neutral conditions, and translocated to the nucleus at pH ~6.1 coincident 
      with the appearance of single strand DNA cuts. Inhibition of the mPTP pore with 
      BH4-TAT peptide, calpain inhibition with PD150606, or knockdown (KD) of Bnip3 
      failed to prevent nuclear translocation of these DNase although Bnip3 KD blocked 
      mitochondrial fission. SIGNIFICANCE: These results suggest that 
      caspase-independent DNA fragmentation is precisely regulated and occurs in 
      parallel but independently from programmed necrosis mediated by hypoxia-acidosis.
CI  - Copyright (c) 2012 Elsevier Inc. All rights reserved.
FAU - Thompson, John W
AU  - Thompson JW
AD  - Department of Molecular and Cellular Pharmacology and the Vascular Biology 
      Institute, University of Miami School of Medicine, Miami, FL 33136, USA.
FAU - Graham, Regina M
AU  - Graham RM
FAU - Webster, Keith A
AU  - Webster KA
LA  - eng
GR  - R01 HL044578/HL/NHLBI NIH HHS/United States
GR  - R01 HL072924/HL/NHLBI NIH HHS/United States
GR  - R01 HL44578/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120413
PL  - Netherlands
TA  - Life Sci
JT  - Life sciences
JID - 0375521
RN  - 0 (Apoptosis Inducing Factor)
RN  - EC 3.1.- (Endodeoxyribonucleases)
RN  - EC 3.1.22.1 (deoxyribonuclease II)
SB  - IM
MH  - *Acidosis
MH  - Animals
MH  - Animals, Newborn
MH  - *Apoptosis
MH  - Apoptosis Inducing Factor/metabolism
MH  - Blotting, Western
MH  - *Cell Hypoxia
MH  - Cell Nucleus/metabolism
MH  - Cells, Cultured
MH  - Endodeoxyribonucleases/*metabolism
MH  - Enzyme Activation
MH  - Immunohistochemistry
MH  - Myocardium/cytology/enzymology/metabolism
MH  - Protein Transport
MH  - Rats
PMC - PMC3638004
MID - NIHMS402853
EDAT- 2012/04/25 06:00
MHDA- 2012/11/02 06:00
PMCR- 2013/09/17
CRDT- 2012/04/25 06:00
PHST- 2011/10/13 00:00 [received]
PHST- 2012/01/24 00:00 [revised]
PHST- 2012/03/21 00:00 [accepted]
PHST- 2012/04/25 06:00 [entrez]
PHST- 2012/04/25 06:00 [pubmed]
PHST- 2012/11/02 06:00 [medline]
PHST- 2013/09/17 00:00 [pmc-release]
AID - S0024-3205(12)00172-5 [pii]
AID - 10.1016/j.lfs.2012.03.034 [doi]
PST - ppublish
SO  - Life Sci. 2012 Sep 17;91(7-8):223-9. doi: 10.1016/j.lfs.2012.03.034. Epub 2012 
      Apr 13.