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Death and Rescue. 未知死 焉知生. Regulation of cardiac myocyte cell death. Lin GH. Death pathway. there are two principal forms of cell death:. Necrosis & apoptosis. Myocyte death as a contributing factor to cardiac pathology. infarction. Ischemic Injury and Myocyte Death.

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death and rescue

Death and Rescue

未知死

焉知生

Regulation of cardiac myocyte cell death

Lin GH

death pathway
Death pathway

there are two principal forms of cell death:

Necrosis & apoptosis

slide3

Myocyte death as a contributing factor to cardiac pathology

infarction

Ischemic Injury and Myocyte Death

There is evidence that apoptosis precedes necrosis and constitutes the prevailing form of myocyte death.

slide4

Initiator caspases

Caspases as the Effector

Machinery of Apoptosis

Effector caspases

Other caspases

cysteine-dependent aspartate-directed proteases

slide5

Caspase cascades are highly ordered

Initiator caspases

effector caspases

positive feedback

slide6

Target proteins for caspases

nuclear proteins

Regulatory proteins

Cytoskeletal proteins

slide7

Apoptotic death pathway

Mitochondrion-

dependent

Intrinsic pathway

Receptor-dependent

Extrinsic pathway

slide8

Mechanisms of Caspase Activation

Activation of caspases

may take place either within death receptor complexes of the

cytoplasmic membrane or by a mitochondrion-dependent

mechanism within the cytosol

slide9

Death Receptor Pathway

death domain-mediated protein interactions

slide11

Mitochondrial Pathway

Schematic diagram showing the mechanism of cytochrome c–dependent caspase activation

apoptosis-inducing factor (AIF).

slide12

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

slide13

Apaf-1 and activation of caspase-9

cytochrome c interacts with an adapter protein, apoptosis-activating factor (Apaf)-1

slide15

Central role of mitochondria during ischemia and reperfusion

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

slide16

The mitochondrial permeability transition pore

cyclophilin D (Cyp-D)

VDAC, voltage-dependent anion channel

ANT, adenine nucleotide translocase

slide17

The Bcl-2 family of proteins are key regulators of the mitochondrial death pathway.

Regulatory Proteins

----Bcl-2 Protein Family

Mediate both proapoptotic

and antiapoptotic regulation

Bcl-xL

Bax

Bcl-2

BH1 (red), BH2 (orange), BH3 (green), and BH4 (yellow)

slide20

Inhibitor of Apoptosis Proteins

X-linked IAP

neuronal IAP

c-IAP1

c-IAP2

survivin

-

caspase activity

caspase activation not only requires proteolytic cleavage of the enzymes themselves, but removal of inhibitory influences (IAPs) is also necessary.

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.

slide21

Signal Transduction

The commitment to apoptosis is influenced by protein kinase cascades

that may be activated in the cell. whereas some protein kinases are implicated in cytoprotection, and others enhance cell death.

Signal transduction pathways implicated in the regulation of cell survival and apoptosis

slide22

Modulation of myocyte cell death

Phosphatidylinositol 3’-kinase

The pathway that is most clearly implicated in cytoprotection

in all cell types is the PI3K pathway This pathway is potently activated by insulin or insulin-like growth factor-1 (IGF-1).

slide24

Mitogen-activated protein kinases

There are three well-characterized MAPK subfamilies that have already been mentioned, the ERKs, JNKs, and p38-MAPKs, all of which influence cell survival

slide25

Toward Antiapoptosis as a New Treatment Modality

Targets for Intervention

Initiation, regulation, and effector mechanisms offer potential molecular targets for antiapoptotic intervention.

slide26

Antiapoptotic strategies

Decoy receptor

Inhibitors of

stress-activated

protein kinases

PI3K, ERK

signaling pathway

ARC

IAPs

BcL-2 family proteins

FasL: Fas ligand; cyt. C: cytochrome c; ARC: apoptosis repressor with a caspase recruitment domain; AIF:apoptosis-inducing factor.

slide27

Antiapoptotic strategies

Targeting the Proapoptotic Stimulus Acting on

the Myocyte

B-blocking agents, carvedilo ,angiotensin-converting enzyme inhibitors, reducing oxidative stress ,inhibition of death receptor stimulation

Promotion of Antiapoptotic Signaling

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),

Targeting Proapoptotic 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 the Downstream Execution Phase of Apoptosis

Inhibition of downstream caspases (caspase-3, -6, or -7)

slide28

Thank you !

Lin GH

2004/0924