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Ischemic preconditioning: protection against myocardial necrosis and apoptosis.

Iliodromitis EK, Lazou A, Kremastinos DT - Vasc Health Risk Manag (2007)

Bottom Line: Apoptosis, a genetically programmed form of cell death, has been associated with cardiomyocyte cell loss in a variety of cardiac pathologies, including cardiac failure and those related to ischemia/reperfusion injury.While ischemic preconditioning significantly reduces DNA fragmentation and apoptotic myocyte death associated with ischemia-reperfusion, the potential mechanisms underlying this effect have not been fully clarified.A comprehensive understanding of these mechanisms and application to clinical scenarios will provide new directions in research and translate this information into new treatment approaches for reducing the extent of ischemia/reperfusion injury.

View Article: PubMed Central - PubMed

Affiliation: 2nd University Department of Cardiology, Medical School, University of Athens, Greece.

ABSTRACT
The phenomenon of ischemic preconditioning has been recognized as one of the most potent mechanisms to protect against myocardial ischemic injury. In experimental animals and humans, a brief period of ischemia has been shown to protect the heart from more prolonged episodes of ischemia, reducing infarct size, attenuating the incidence, and severity of reperfusion-induced arrhythmias, and preventing endothelial cell dysfunction. Although the exact mechanism of ischemic preconditioning remains obscure, several reports indicate that this phenomenon may be a form of receptor-mediated cardiac protection and that the underlying intracellular signal transduction pathways involve activation of a number of protein kinases, including protein kinase C, and mitochondrial K(ATP) channels. Apoptosis, a genetically programmed form of cell death, has been associated with cardiomyocyte cell loss in a variety of cardiac pathologies, including cardiac failure and those related to ischemia/reperfusion injury. While ischemic preconditioning significantly reduces DNA fragmentation and apoptotic myocyte death associated with ischemia-reperfusion, the potential mechanisms underlying this effect have not been fully clarified. A comprehensive understanding of these mechanisms and application to clinical scenarios will provide new directions in research and translate this information into new treatment approaches for reducing the extent of ischemia/reperfusion injury.

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Related in: MedlinePlus

Schematic representation of the mitochondrial death (intrinsic) pathway leading to the formation of apoptosome, activation of caspases and apoptosis.
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fig3: Schematic representation of the mitochondrial death (intrinsic) pathway leading to the formation of apoptosome, activation of caspases and apoptosis.

Mentions: There are two principal pathways that lead to caspase activation: the extrinsic and intrinsic cell death pathways (Danial and Korshmeyer 2004). The extrinsic pathway requires the activation of cell surface death receptors (DRs) by specific ligands, and allows the cell to respond directly to the immediate environment (Figure 2). The vast majority of death receptors belong to the tumor necrosis factor receptor (TNFR) superfamily, which includes Fas, TNFR1, and DR3–DR6. The binding of death ligands, such as Fas ligand or TNF-α, to their cognate receptors at the plasma membrane causes homotrimerization of the receptor and recruitment of specific adaptor proteins, such as Fas-associated death domain and procaspase-8, into a death-inducing signaling complex (DISC). This, in turn, leads to activation of initiator caspase-8, which subsequently activates effector caspases 3, 6, and 7 (Hirata et al 1998; Danial and Korshmeyer 2004). In contrast, in the intrinsic pathway (Figure 3), the mitochondria detect and respond to unfavorable changes in the internal environment and play a central role in the integration and execution of a wide variety of apoptotic signals. The mitochondria provide the energy required for execution of the apoptotic program and release of pro-apoptotic proteins such as cytochrome c, endonuclease G, and apoptosis-inducing factor. Release of these substances occurs during opening of the mitochondrial permeability transition (MPT) pore, a large non-selective ion channel in the outer mitochondrial membrane. Gating of the MPT pore is controlled by a combination of calcium, redox potential, pH and transmembrane voltage; when the MPT is opened, the normally impervious mitochondrial membrane undergoes a reversible transition to permeability (Zoratti and Szab’o 1995; Chelli et al 2001). Either brief or sustained MPT opening can lead to apoptosis (Bishopric et al 2001). On release from mitochondria, cytochrome c forms a complex with procaspase-9 and a cytosolic cofactor, Apaf-1 (Li et al 1997; Zou et al 1999). In the presence of sufficient ATP, caspase-9 undergoes autocatalytic cleavage to create an active ‘apoptosome’ that cleaves caspase-3 and initiates the apoptotic program. Thus, the extrinsic and intrinsic pathways have different initiator caspases but converge at the level of the effector caspases.


Ischemic preconditioning: protection against myocardial necrosis and apoptosis.

Iliodromitis EK, Lazou A, Kremastinos DT - Vasc Health Risk Manag (2007)

Schematic representation of the mitochondrial death (intrinsic) pathway leading to the formation of apoptosome, activation of caspases and apoptosis.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2291307&req=5

fig3: Schematic representation of the mitochondrial death (intrinsic) pathway leading to the formation of apoptosome, activation of caspases and apoptosis.
Mentions: There are two principal pathways that lead to caspase activation: the extrinsic and intrinsic cell death pathways (Danial and Korshmeyer 2004). The extrinsic pathway requires the activation of cell surface death receptors (DRs) by specific ligands, and allows the cell to respond directly to the immediate environment (Figure 2). The vast majority of death receptors belong to the tumor necrosis factor receptor (TNFR) superfamily, which includes Fas, TNFR1, and DR3–DR6. The binding of death ligands, such as Fas ligand or TNF-α, to their cognate receptors at the plasma membrane causes homotrimerization of the receptor and recruitment of specific adaptor proteins, such as Fas-associated death domain and procaspase-8, into a death-inducing signaling complex (DISC). This, in turn, leads to activation of initiator caspase-8, which subsequently activates effector caspases 3, 6, and 7 (Hirata et al 1998; Danial and Korshmeyer 2004). In contrast, in the intrinsic pathway (Figure 3), the mitochondria detect and respond to unfavorable changes in the internal environment and play a central role in the integration and execution of a wide variety of apoptotic signals. The mitochondria provide the energy required for execution of the apoptotic program and release of pro-apoptotic proteins such as cytochrome c, endonuclease G, and apoptosis-inducing factor. Release of these substances occurs during opening of the mitochondrial permeability transition (MPT) pore, a large non-selective ion channel in the outer mitochondrial membrane. Gating of the MPT pore is controlled by a combination of calcium, redox potential, pH and transmembrane voltage; when the MPT is opened, the normally impervious mitochondrial membrane undergoes a reversible transition to permeability (Zoratti and Szab’o 1995; Chelli et al 2001). Either brief or sustained MPT opening can lead to apoptosis (Bishopric et al 2001). On release from mitochondria, cytochrome c forms a complex with procaspase-9 and a cytosolic cofactor, Apaf-1 (Li et al 1997; Zou et al 1999). In the presence of sufficient ATP, caspase-9 undergoes autocatalytic cleavage to create an active ‘apoptosome’ that cleaves caspase-3 and initiates the apoptotic program. Thus, the extrinsic and intrinsic pathways have different initiator caspases but converge at the level of the effector caspases.

Bottom Line: Apoptosis, a genetically programmed form of cell death, has been associated with cardiomyocyte cell loss in a variety of cardiac pathologies, including cardiac failure and those related to ischemia/reperfusion injury.While ischemic preconditioning significantly reduces DNA fragmentation and apoptotic myocyte death associated with ischemia-reperfusion, the potential mechanisms underlying this effect have not been fully clarified.A comprehensive understanding of these mechanisms and application to clinical scenarios will provide new directions in research and translate this information into new treatment approaches for reducing the extent of ischemia/reperfusion injury.

View Article: PubMed Central - PubMed

Affiliation: 2nd University Department of Cardiology, Medical School, University of Athens, Greece.

ABSTRACT
The phenomenon of ischemic preconditioning has been recognized as one of the most potent mechanisms to protect against myocardial ischemic injury. In experimental animals and humans, a brief period of ischemia has been shown to protect the heart from more prolonged episodes of ischemia, reducing infarct size, attenuating the incidence, and severity of reperfusion-induced arrhythmias, and preventing endothelial cell dysfunction. Although the exact mechanism of ischemic preconditioning remains obscure, several reports indicate that this phenomenon may be a form of receptor-mediated cardiac protection and that the underlying intracellular signal transduction pathways involve activation of a number of protein kinases, including protein kinase C, and mitochondrial K(ATP) channels. Apoptosis, a genetically programmed form of cell death, has been associated with cardiomyocyte cell loss in a variety of cardiac pathologies, including cardiac failure and those related to ischemia/reperfusion injury. While ischemic preconditioning significantly reduces DNA fragmentation and apoptotic myocyte death associated with ischemia-reperfusion, the potential mechanisms underlying this effect have not been fully clarified. A comprehensive understanding of these mechanisms and application to clinical scenarios will provide new directions in research and translate this information into new treatment approaches for reducing the extent of ischemia/reperfusion injury.

Show MeSH
Related in: MedlinePlus