Death and Rescue
未知死
焉知生
Regulation of cardiac myocyte cell death
Lin GH
Death pathwaythere are two principal forms of cell death:
Necrosis & apoptosis
Myocyte death as a contributing factor to cardiac pathology
Ischemic Injury and Myocyte DeathThere is evidence that apoptosis precedes necrosis and constitutes the prevailing form of myocyte death.
infarction
Caspases as the Effector Machinery of Apoptosis
Initiator caspases
Other caspases
Effector caspases
cysteine-dependent aspartate-directed proteases
Caspase cascades are highly ordered
effector caspases
positive feedback
Initiator caspases
Target proteins for caspases
nuclear proteins
Cytoskeletal proteins
Regulatory proteins
Apoptotic death pathway
Receptor-dependent
Mitochondrion-dependent
Extrinsic pathway
Intrinsic pathway
Mechanisms of Caspase Activation
Activation of caspasesmay take place either within death receptor complexes of thecytoplasmic membrane or by a mitochondrion-dependentmechanism within the cytosol
Death Receptor Pathway
death domain-mediated protein interactions
The extrinsic pathway through death receptors
Mitochondrial Pathway
Schematic diagram showing the mechanism of cytochrome c–dependent caspase activation
apoptosis-inducing factor (AIF).
Intrinsic pathway through the mitochondria
Intracellular stresses such as increased oxidative stress, which may derive from the mitochondria themselves, activate the mitochondrial death pathway.
apoptosome
Apaf-1 and activation of caspase-9
cytochrome c interacts with an adapter protein, apoptosis-activating factor (Apaf)-1
Morphological changes in mitochondria during cytochrome c release
Cytochrome c and the mitochondrial permeability transition pore
opening of the MPTP may also influence cell death by effecting the release of cyt c and other apoptotic factors from the mitochondrial intermembrane space
Central role of mitochondria during ischemia and reperfusion
The mitochondrial permeability transition pore
cyclophilin D (Cyp-D)VDAC, voltage-dependent anion channelANT, adenine nucleotide translocase
Regulatory Proteins----Bcl-2 Protein Family
Mediate both proapoptoticand antiapoptotic regulation
The Bcl-2 family of proteins are key regulators of the mitochondrial death pathway.
Bcl-2 Bcl-xL Bax
BH1 (red), BH2 (orange), BH3 (green), and BH4 (yellow)
Mechanisms suggested to mediate the antiapoptotic effect of bcl-2
Model for the mechanism of action of Bcl-2 family proteins
X-linked IAP
neuronal IAP
c-IAP1
c-IAP2
survivin
caspase activity
Since the levels of expression of IAPs (and other inhibitory proteins) appear to be high in the heart, modulation of these proteins may be a significant aspect of cardiac myocyte apoptosis.
caspase activation not only requires proteolytic cleavage of the enzymes themselves, but removal of inhibitory influences (IAPs) is also necessary.
Inhibitor of Apoptosis Proteins
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Signal Transduction
Signal transduction pathways implicated in the regulation of cell survival and apoptosis
The commitment to apoptosis is influenced by protein kinase cascadesthat may be activated in the cell. whereas some protein kinases are implicated in cytoprotection, and others enhance cell death.
The pathway that is most clearly implicated in cytoprotectionin all cell types is the PI3K pathway This pathway is potently activated by insulin or insulin-like growth factor-1 (IGF-1).
Modulation of myocyte cell death
Phosphatidylinositol 3’-kinase
Akt Signaling
There are three well-characterized MAPK subfamilies that have already been mentioned, the ERKs, JNKs, and p38-MAPKs, all of which influence cell survival
Mitogen-activated protein kinases
Toward Antiapoptosis as a New Treatment Modality
Targets for Intervention
Initiation, regulation, and effector mechanisms offer potential molecular targets for antiapoptotic intervention.
Antiapoptotic strategies
FasL: Fas ligand; cyt. C: cytochrome c; ARC: apoptosis repressor with a caspase recruitment domain; AIF:apoptosis-inducing factor.
Decoy receptor
ARC
IAPs
BcL-2 family proteins
Inhibitors ofstress-activated protein kinases
PI3K, ERK signaling pathway
Targeting the Proapoptotic Stimulus Acting onthe Myocyte
B-blocking agents, carvedilo ,angiotensin-converting enzyme inhibitors, reducing oxidative stress ,inhibition of death receptor stimulation
Bcl-2 protein family (eg, Bcl-2 or Bcl-xL), apoptosis repressor with a caspase recruitment domain, decoy receptors ,growth factors ( insulin-like growth factor-1, cardiotrophin-1, neuregulins),
Promotion of Antiapoptotic Signaling
proapoptotic members of the Bcl-2 protein family such as Bax, Bad, and Bid, synthetic drugs interfere with the proapoptotic activity of adaptor protein , inhibition of MPTP and intracellular signaling pathways in promoting apoptosis
Targeting Proapoptotic Signaling
Antiapoptotic strategies
Targeting the Downstream Execution Phase of Apoptosis
Inhibition of downstream caspases (caspase-3, -6, or -7)
Thank you !
Lin GH2004/0924
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