Sensitivity to apoptosis signal, clearance rate, and ultrastructure of fas ligand-induced apoptosis in in vivo adult cardiac cells.
BACKGROUND
Sensitivity to apoptotic signals, the clearance rate of apoptosis, and the apoptotic ultrastructure have not been studied in cells of the in vivo adult heart.


RESULTS
To minimize the systemic influence, soluble Fas ligand was injected directly into in vivo rat hearts and livers (as the control) at concentrations of 0, 0.5, 2, and 5 microg/mL (groups C, F0.5, F2, and F5). Apoptotic cardiomyocytes and apoptotic noncardiomyocytes of the heart were identified with similar incidences only in F5. Their incidences peaked at 12 hours after injection (2.0+/-0.09% in cardiomyocytes) and diminished markedly 24 hours later. Caspase-3 was activated only in F5. Boc-Asp-fmk, a pancaspase inhibitor, inhibited apoptosis, suggesting that the apoptosis sensitivity was regulated upstream of caspase-3. Apoptotic noncardiomyocytes showed typical ultrastructure. In addition to the typical ultrastructure, such as cellular shrinkage, chromatin condensation, and apoptotic bodies, however, apoptotic cardiomyocytes showed unique features: doughnut-like, but not half-moon- or crescent-like, chromatin condensation; frequent plasma membrane rupture even during the early stage; condensed mitochondria with wrinkled cristae inside; the appearance of cytoplasmic lipid-like droplets; and myofibrillar derangement. In the livers, typical apoptosis was induced in hepatocytes and nonhepatocytes of the liver even in the F0.5 group, which were cleared 24 hours later.


CONCLUSIONS
Compared with liver cells, cardiomyocytes as well as noncardiomyocytes of the heart are more resistant against the apoptotic signal, but the clearance is similarly rapid (within 24 hours). The ultrastructure of apoptotic cardiomyocytes is unique. These findings provide new insights into the dynamics of cell death in the heart.
Hayakawa
Kenji
K
Second Department of Internal Medicine, Gifu University School of Medicine, Gifu, Japan.
Takemura
Genzou
G
Koda
Masahiko
M
Kawase
Yukinori
Y
Maruyama
Rumi
R
Li
Yiwen
Y
Minatoguchi
Shinya
S
Fujiwara
Takako
T
Fujiwara
Hisayoshi
H
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D053938:DNA Fragmentation; D053222:Fas Ligand Protein; D006321:Heart / Q000187:drug effects; D006333:Heart Failure / Q000473:pathology; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects; D007700:Kinetics; D008297:Male; D008562:Membrane Glycoproteins / Q000633:toxicity*; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism / Q000648:ultrastructure*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction
D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases