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

Abstract

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 g/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 (2.0Ϯ0.09% 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. (Circulation. 2002;105:3039-3045.)

Fas pathway is a critical mediator of cardiac myocyte death and MI during ischemia-reperfusion in vivo

“…It is interesting to consider why only low levels of cardiac myocyte apoptosis have been observed in response to soluble FasL in some previous studies (17,(55)(56)(57). We speculate that this may be the result of inadequate levels and/or presentation of the ligand.…”

Combined therapy with cardioprotective cytokine administration and antiapoptotic gene transfer in postinfarction heart failure

“…The interaction of Fas with Fas ligand is an important trigger for apoptosis in many cell types, including cells related to the immune system and granulation tissue cells (17,23). However, an adult cardiomyocyte is reportedly very insensitive to Fasmediated apoptosis (12,36).…”

Importance of antioxidant and antiapoptotic effects of β-receptor blockers in heart failure therapy

“…The rate of apoptosis is in the 80 -250/10 5 cardiomyocytes range in the human failing heart (28). However, despite the slow rate of apoptosis, given the short duration (Ͻ24 h) required for a myocyte to undergo apoptosis and cleared from the tissue (14), the programmed cell death is considered pathologically important and may contribute a significant loss of myocytes over a long period of time. The importance of cardiac myocyte apoptosis in heart failure was further demonstrated by Wencker et al (48), using transgenic mice, in that low levels of myocyte apoptosis (23/10 5 ) were induced by conditional overexpression of caspase 8 in the heart.…”