PMID- 10212235
OWN - NLM
STAT- MEDLINE
DCOM- 19990603
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 18
DP  - 1999 Apr 30
TI  - Glucose uptake and glycolysis reduce hypoxia-induced apoptosis in cultured 
      neonatal rat cardiac myocytes.
PG  - 12567-75
AB  - Myocardial ischemia/reperfusion is well recognized as a major cause of apoptotic 
      or necrotic cell death. Neonatal rat cardiac myocytes are intrinsically resistant 
      to hypoxia-induced apoptosis, suggesting a protective role of energy-generating 
      substrates. In the present report, a model of sustained hypoxia of primary 
      cultures of Percoll-enriched neonatal rat cardiac myocytes was used to study 
      specifically the modulatory role of extracellular glucose and other intermediary 
      substrates of energy metabolism (pyruvate, lactate, propionate) as well as 
      glycolytic inhibitors (2-deoxyglucose and iodoacetate) on the induction and 
      maintenance of apoptosis. In the absence of glucose and other substrates, hypoxia 
      (5% CO2 and 95% N2) caused apoptosis in 14% of cardiac myocytes at 3 h and in 22% 
      of cells at 6-8 h of hypoxia, as revealed by sarcolemmal membrane blebbing, 
      nuclear fragmentation, and chromatin condensation (Hoechst staining), terminal 
      deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, 
      and DNA laddering. This was accompanied by translocation of cytochrome c from the 
      mitochondria to the cytosol and cleavage of the death substrate poly(ADP-ribose) 
      polymerase. Cleavage of poly(ADP-ribose) polymerase and DNA laddering were 
      prevented by preincubation with the caspase inhibitors 
      benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD-fmk) and 
      benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl ketone (zDEVD-fmk), indicating 
      activation of caspases in the apoptotic process. The caspase inhibitor zDEVD-fmk 
      also partially inhibited cytochrome c translocation. The presence of as little as 
      1 mM glucose, but not pyruvate, lactate, or propionate, before hypoxia prevented 
      apoptosis. Inhibiting glycolysis by 2-deoxyglucose or iodoacetate, in the 
      presence of glucose, reversed the protective effect of glucose. This study 
      demonstrates that glycolysis of extracellular glucose, and not other metabolic 
      pathways, protects cardiac myocytes from hypoxic injury and subsequent apoptosis.
FAU - Malhotra, R
AU  - Malhotra R
AD  - Department of Internal Medicine, Division of Nephrology, University of Michigan 
      Medical Center and the Ann Arbor Veterans Affairs Medical Center, Ann Arbor, 
      Michigan 48109, USA.
FAU - Brosius, F C 3rd
AU  - Brosius FC 3rd
LA  - eng
GR  - HL060156/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - *Apoptosis
MH  - *Cell Hypoxia
MH  - Cells, Cultured
MH  - Glucose/*metabolism
MH  - *Glycolysis
MH  - Myocardium/cytology/*metabolism
MH  - Poly(ADP-ribose) Polymerases/metabolism
MH  - Rats
MH  - Rats, Wistar
MH  - Substrate Specificity
EDAT- 1999/04/23 02:02
MHDA- 2001/03/28 10:01
CRDT- 1999/04/23 02:02
PHST- 1999/04/23 02:02 [pubmed]
PHST- 2001/03/28 10:01 [medline]
PHST- 1999/04/23 02:02 [entrez]
AID - S0021-9258(19)73390-0 [pii]
AID - 10.1074/jbc.274.18.12567 [doi]
PST - ppublish
SO  - J Biol Chem. 1999 Apr 30;274(18):12567-75. doi: 10.1074/jbc.274.18.12567.