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(Circulation. 2002;105:3039.)
© 2002 American Heart Association, Inc.

Basic Science Reports

Sensitivity to Apoptosis Signal, Clearance Rate, and Ultrastructure of Fas Ligand-Induced Apoptosis in In Vivo Adult Cardiac Cells

Kenji Hayakawa, MD; Genzou Takemura, MD, PhD; Masahiko Koda, MD; Yukinori Kawase, MD; Rumi Maruyama, BS; Yiwen Li, MD; Shinya Minatoguchi, MD, PhD; Takako Fujiwara, MD, PhD; Hisayoshi Fujiwara, MD, PhD

From the Second Department of Internal Medicine, Gifu University School of Medicine, Gifu, and the Department of Food Science, Kyoto Women’s University, Kyoto (T.F.), Japan.

Correspondence to Hisayoshi Fujiwara, MD, PhD, Second Department of Internal Medicine, Gifu University School of Medicine, 40 Tsukasa-Machi, Gifu 500-8705, Japan. E-mail gifuim-gif@ umin.ac.jp

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.

Methods and 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 µg/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.

Key Words: apoptosis • myocytes • ligands

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