Unresolved Issues Regarding the Role of Apoptosis in the Pathogenesis of Ischemic Injury and Heart Failure

Elsässer, Albrecht; Suzuki, Keisuke; Schaper, Jutta

doi:10.1006/jmcc.2000.1125

Cited by 131 publications

(65 citation statements)

References 91 publications

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“…1 The present study has shown that the clearance rate of apoptotic cardiomyocytes is Ͻ24 hours (1 day). Therefore, despite the very low incidence of cardiomyocytes resulting from low sensitivity and rapid clearance, apoptosis may make a significant contribution to the progression of chronic heart failure.…”

Section: Discussionsupporting

confidence: 48%

“…[1][2][3] Thus, we suggest that (1) cardiomyocytes may be resistant to apoptosis signals and apoptosis may be induced only when the degree of the signals overcomes the high threshold or that (2) the clearance rate of apoptotic cardiomyocytes may be too rapid in the in vivo beating heart to be easily detected despite their considerable occurrence. At present, however, there is no evidence on this issue.…”

mentioning

confidence: 94%

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

et al. 2002

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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.)

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Section: Discussionsupporting

confidence: 48%

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confidence: 94%

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

et al. 2002

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“…34 Cumulative levels of apoptosis identified in the failing heart suggest that acute myocardial infarction promotes massive apoptosis of cardiomyocytes because of a primary lack of oxygen and/or a reperfusion-induced hyperemia that is associated with free radical production. 35 We conclude that in the isolated adult rat cardiomyocyte model of hypoxic PC, PI-3 kinase and Akt signaling pathways are required for the maintenance of mitochondria-stabilizing Bcl-2 protein, which subsequently antagonize mitochondrial dysfunction of cytochrome c release and caspase activation, thereby antagonizing apoptosis.…”

Section: Discussionmentioning

confidence: 76%

Role of Akt Signaling in Mitochondrial Survival Pathway Triggered by Hypoxic Preconditioning

et al. 2004

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Background-The signaling pathways that control ischemia/reperfusion-induced cardiomyocyte apoptosis in heart have not been fully defined. In this study, we investigated whether Akt signaling has a role in the antiapoptotic pathways of preconditioning against hypoxia/reoxygenation (H/R). Methods and Results-Primary cultures of adult rat ventricular myocytes (ARVMs) were subjected to preconditioning (PC) by exposing the cells to 10 minutes of hypoxia followed by 30 minutes of reoxygenation. Non-PC and PC myocytes were subjected to 90 minutes of hypoxia followed by 120 minutes of reoxygenation. Hypoxic-PC protected the myocytes from subsequent H/R injury, as evidenced by decreased apoptosis and LDH release and increased cell viability. H/R-induced cytochrome c release and activation of caspase-3 and -9 were blocked by PC. This protective effect was inhibited by treating the cells with LY294002 (50 mol/L), a PI3 kinase inhibitor, for 10 minutes before and during PC. PC also induced phosphorylation of Akt and BAD. Protein levels of Bcl-2 in mitochondria were maintained in PC. ARVMs were infected with either a control adenovirus (Adeno lac-Z), an adenovirus expressing dominantnegative Akt, or an adenovirus expressing constitutively active Akt. Ectopic overexpression of constitutively active Akt protected ARVMs from apoptosis induced by hypoxia/reoxygenation compared with Adeno lac-Z. In contrast, dominant negative Akt overexpression abolished the antiapoptotic effect of PC. Conclusions-Our data demonstrated that in adult cardiomyocytes, the antiapoptotic effect of PC against H/R requires Akt signaling leading to phosphorylation of BAD, inhibition of cytochrome c release, and prevention of caspase activation.

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“…CARDIOCYTE APOPTOSIS, or programmed cell death, is important in the pathogenesis of ischemic heart disease (7,10,16,21,28). Apoptotic cells are prominent in the border zone of an ischemic area (10) and have been documented in acute human myocardial infarction (32).…”

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confidence: 99%

Preconditioning blocks cardiocyte apoptosis: role of K_ATPchannels and PKC-ε

Liu

Zhang

Zhu

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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The aims of this study were to determine whether preconditioning blocks cardiocyte apoptosis and to determine the role of mitochondrial ATP-sensitive K+(KATP) channels and the protein kinase C ε-isoform (PKC-ε) in this effect. Ventricular myocytes from 10-day-old chick embryos were used. In the control series, 10 h of simulated ischemia followed by 12 h of reoxygenation resulted in 42 ± 3% apoptosis ( n = 8). These results were consistent with DNA laddering and TdT-mediated dUTP nick-end labeling (TUNEL) assay. Preconditioning, elicited with three cycles of 1 min of ischemia separated by 5 min of reoxygenation before subjection to prolonged simulated ischemia, markedly attenuated the apoptotic process (28 ± 4%, n = 8). The selective mitochondrial KATP channel opener diazoxide (400 μmol/l), given before ischemia, mimicked preconditioning effects to prevent apoptosis (22 ± 4%, n = 6). Pretreatment with 5-hydroxydecanoate (100 μmol/l), a selective mitochondrial KATP channel blocker, abolished preconditioning (42 ± 2%, n = 6). In addition, the effects of preconditioning and diazoxide were blocked with the specific PKC inhibitors Gö-6976 (0.1 μmol/l) or chelerythrine (4 μmol/l), given at simulated ischemia and reoxygenation. Furthermore, preconditioning and diazoxide selectively activated PKC-ε in the particulate fraction before simulated ischemia without effect on the total fraction, cytosolic fraction, and PKC δ-isoform. The specific PKC activator phorbol 12-myristate 13-acetate (0.2 μmol/l), added during simulated ischemia and reoxygenation, mimicked preconditioning to block apoptosis. Opening mitochondrial KATP channels blocks cardiocyte apoptosis via activating PKC-ε in cultured ventricular myocytes. Through this signal transduction, preconditioning blocks apoptosis and preserves cardiac function in ischemia-reperfusion.

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Unresolved Issues Regarding the Role of Apoptosis in the Pathogenesis of Ischemic Injury and Heart Failure

Cited by 131 publications

References 91 publications

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

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

Role of Akt Signaling in Mitochondrial Survival Pathway Triggered by Hypoxic Preconditioning

Preconditioning blocks cardiocyte apoptosis: role of K_ATPchannels and PKC-ε

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Unresolved Issues Regarding the Role of Apoptosis in the Pathogenesis of Ischemic Injury and Heart Failure

Cited by 131 publications

References 91 publications

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

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

Role of Akt Signaling in Mitochondrial Survival Pathway Triggered by Hypoxic Preconditioning

Preconditioning blocks cardiocyte apoptosis: role of KATPchannels and PKC-ε

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Preconditioning blocks cardiocyte apoptosis: role of K_ATPchannels and PKC-ε