PMID- 17045908
OWN - NLM
STAT- MEDLINE
DCOM- 20061121
LR  - 20221109
IS  - 1558-3597 (Electronic)
IS  - 0735-1097 (Linking)
VI  - 48
IP  - 8
DP  - 2006 Oct 17
TI  - Attenuation by metallothionein of early cardiac cell death via suppression of 
      mitochondrial oxidative stress results in a prevention of diabetic 
      cardiomyopathy.
PG  - 1688-97
AB  - OBJECTIVES: We aimed to test whether attenuation of early-phase cardiac cell 
      death can prevent diabetic cardiomyopathy. BACKGROUND: Our previous study showed 
      that cardiac apoptosis as a major early cellular response to diabetes is induced 
      by hyperglycemia-derived oxidative stress that activates a mitochondrial 
      cytochrome c-mediated caspase-3 activation pathway. Metallothionein (MT) as a 
      potent antioxidant prevents the development of diabetic cardiomyopathy. METHODS: 
      Diabetes was induced by a single dose of streptozotocin (STZ) (150 mg/kg) in 
      cardiac-specific, metallothionein-overexpressing transgenic (MT-TG) mice and 
      wild-type (WT) controls. On days 7, 14, and 21 after STZ treatment, cardiac 
      apoptosis was examined by terminal deoxynucleotidyl transferase-mediated dUTP 
      nick end labeling (TUNEL) assay and caspase-3 activation. Cardiomyopathy was 
      evaluated by cardiac ultrastructure and fibrosis in the diabetic mice 6 months 
      after STZ treatment. RESULTS: A significant reduction in diabetes-induced 
      increases in TUNEL-positive cells, caspase-3 activation, and cytochrome c release 
      from mitochondria was observed in the MT-TG mice as compared to WT mice. Cardiac 
      protein nitration (3-nitrotyrosine [3-NT]) and lipid peroxidation were 
      significantly increased, and there was an increase in mitochondrial oxidized 
      glutathione and a decrease in mitochondrial reduced glutathione in the WT, but 
      not in the MT-TG, diabetic mice. Double staining for cardiomyocytes with alpha 
      sarcomeric actin and caspase-3 or 3-NT confirmed the cardiomyocyte-specific 
      effects. A significant prevention of diabetic cardiomyopathy and enhanced animal 
      survival were observed in the MT-TG diabetic mice as compared to WT diabetic 
      mice. CONCLUSIONS: These results suggest that attenuation of early-phase cardiac 
      cell death by MT results in a significant prevention of the development of 
      diabetic cardiomyopathy. This process is mediated by MT suppression of 
      mitochondrial oxidative stress.
FAU - Cai, Lu
AU  - Cai L
AD  - Department of Medicine, the University of Louisville, Louisville, Kentucky, USA. 
      L0cai001@louisville.edu
FAU - Wang, Yuehui
AU  - Wang Y
FAU - Zhou, Guihua
AU  - Zhou G
FAU - Chen, Teresa
AU  - Chen T
FAU - Song, Ye
AU  - Song Y
FAU - Li, Xiaokun
AU  - Li X
FAU - Kang, Y James
AU  - Kang YJ
LA  - eng
GR  - HL59225/HL/NHLBI NIH HHS/United States
GR  - HL63760/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 - 20060927
PL  - United States
TA  - J Am Coll Cardiol
JT  - Journal of the American College of Cardiology
JID - 8301365
RN  - 0 (Actins)
RN  - 0 (Antioxidants)
RN  - 3604-79-3 (3-nitrotyrosine)
RN  - 42HK56048U (Tyrosine)
RN  - 9007-43-6 (Cytochromes c)
RN  - 9038-94-2 (Metallothionein)
RN  - EC 3.4.22.- (Caspase 3)
RN  - GAN16C9B8O (Glutathione)
RN  - ULW86O013H (Glutathione Disulfide)
SB  - IM
MH  - Actins/metabolism
MH  - Animals
MH  - Antioxidants/*metabolism
MH  - Apoptosis/drug effects
MH  - Cardiomyopathies/etiology/*prevention & control
MH  - Caspase 3/metabolism
MH  - Cell Death
MH  - Cytochromes c/metabolism
MH  - Diabetes Mellitus, 
      Experimental/*complications/metabolism/pathology/physiopathology
MH  - Enzyme Activation
MH  - Glutathione/antagonists & inhibitors
MH  - Glutathione Disulfide/metabolism
MH  - Lipid Peroxidation
MH  - Metallothionein/genetics/*metabolism
MH  - Mice
MH  - Mice, Transgenic/genetics
MH  - Mitochondria, Heart/*metabolism
MH  - Myocardium/metabolism/pathology
MH  - *Myocytes, Cardiac
MH  - *Oxidative Stress
MH  - Sarcomeres/metabolism
MH  - Survival Analysis
MH  - Tyrosine/analogs & derivatives/metabolism
EDAT- 2006/10/19 09:00
MHDA- 2006/12/09 09:00
CRDT- 2006/10/19 09:00
PHST- 2006/04/07 00:00 [received]
PHST- 2006/06/15 00:00 [revised]
PHST- 2006/06/19 00:00 [accepted]
PHST- 2006/10/19 09:00 [pubmed]
PHST- 2006/12/09 09:00 [medline]
PHST- 2006/10/19 09:00 [entrez]
AID - S0735-1097(06)01909-7 [pii]
AID - 10.1016/j.jacc.2006.07.022 [doi]
PST - ppublish
SO  - J Am Coll Cardiol. 2006 Oct 17;48(8):1688-97. doi: 10.1016/j.jacc.2006.07.022. 
      Epub 2006 Sep 27.