PMID- 10590251
OWN - NLM
STAT- MEDLINE
DCOM- 19991221
LR  - 20190706
IS  - 1524-4571 (Electronic)
IS  - 0009-7330 (Linking)
VI  - 85
IP  - 12
DP  - 1999 Dec 9
TI  - ARC inhibits cytochrome c release from mitochondria and protects against
      hypoxia-induced apoptosis in heart-derived H9c2 cells.
PG  - e70-7
AB  - Ischemia induces apoptosis as well as necrosis of cardiac myocytes. We recently
      reported the cloning of a cDNA that encodes an apoptotic inhibitor, ARC, that is 
      expressed predominantly in cardiac and skeletal muscle. In the present study, we 
      examined the ability of ARC to protect rat embryonic heart-derived H9c2 cells
      from apoptosis induced by hypoxia, a component of ischemia. We found that H9c2
      cells express ARC and that exposure to hypoxia substantially reduces ARC
      expression while inducing apoptosis. Transfected H9c2 cells in which cytosolic
      ARC protein levels remain elevated during hypoxia were significantly more
      resistant to hypoxia-induced apoptosis than parental H9c2 cells or H9c2 cells
      transfected with a control vector. Loss of endogenous ARC in the cytosol of H9c2 
      cells was associated with translocation of ARC from the cytosol to intracellular 
      membranes, release of cytochrome c from the mitochondria, activation of
      caspase-3, poly(ADP-ribose)polymerase (PARP) cleavage, and DNA fragmentation. All
      of these events were inhibited in H9c2 cells overexpressing ARC when compared
      with control cells. In contrast, caspase inhibitors prevented PARP cleavage but
      not cytochrome c release, suggesting that exogenously expressed ARC acts upstream
      of caspase activation in this model of apoptosis. These results demonstrate that 
      ARC can protect heart myogenic H9c2 cells from hypoxia-induced apoptosis, and
      that ARC prevents cytochrome c release by acting upstream of caspase activation, 
      perhaps at the mitochondrial level.
FAU - Ekhterae, D
AU  - Ekhterae D
AD  - Department of Pathology and Comprehensive Cancer Center, Departments of Internal 
      Medicineand Physiology , University of Michigan Medical School, Ann Arbor, MI
      48109-0938, USA.
FAU - Lin, Z
AU  - Lin Z
FAU - Lundberg, M S
AU  - Lundberg MS
FAU - Crow, M T
AU  - Crow MT
FAU - Brosius, F C 3rd
AU  - Brosius FC 3rd
FAU - Nunez, G
AU  - Nunez G
LA  - eng
GR  - CA-64421/CA/NCI NIH HHS/United States
GR  - CA-64556/CA/NCI NIH HHS/United States
GR  - HL-060156/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Circ Res
JT  - Circulation research
JID - 0047103
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (Cysteine Proteinase Inhibitors)
RN  - 0 (Cytochrome c Group)
RN  - 0 (Muscle Proteins)
RN  - 0 (Nol3 protein, rat)
RN  - EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
RN  - EC 3.4.22.- (Casp3 protein, rat)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspases)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - *Apoptosis/genetics
MH  - Apoptosis Regulatory Proteins
MH  - Caspase 3
MH  - Caspases/metabolism
MH  - Cell Hypoxia/genetics
MH  - Cell Line
MH  - Cysteine Proteinase Inhibitors/*biosynthesis
MH  - Cytochrome c Group/*metabolism
MH  - DNA Fragmentation
MH  - Enzyme Activation/genetics
MH  - Fluorescent Antibody Technique, Indirect
MH  - Immunoblotting
MH  - Mitochondria/metabolism
MH  - Muscle Proteins/*biosynthesis/genetics/metabolism
MH  - Myocardium/*metabolism/pathology
MH  - Poly(ADP-ribose) Polymerases/metabolism
MH  - Rats
MH  - Transfection
EDAT- 1999/12/11 09:00
MHDA- 2001/03/28 10:01
CRDT- 1999/12/11 09:00
PHST- 1999/12/11 09:00 [pubmed]
PHST- 2001/03/28 10:01 [medline]
PHST- 1999/12/11 09:00 [entrez]
AID - 10.1161/01.res.85.12.e70 [doi]
PST - ppublish
SO  - Circ Res. 1999 Dec 9;85(12):e70-7. doi: 10.1161/01.res.85.12.e70.