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