Death and Rescue. æœªçŸ¥æ» ç„‰çŸ¥ç”Ÿ. 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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Regulation of cardiac myocyte cell death
there are two principal forms of cell death:
Necrosis & apoptosis
Ischemic Injury and Myocyte Death
There is evidence that apoptosis precedes necrosis and constitutes the prevailing form of myocyte death.
Caspases as the Effector
Machinery of Apoptosis
cysteine-dependent aspartate-directed proteases
Activation of caspases
may take place either within death receptor complexes of the
cytoplasmic membrane or by a mitochondrion-dependent
mechanism within the cytosol
death domain-mediated protein interactions
Schematic diagram showing the mechanism of cytochrome c–dependent caspase activation
apoptosis-inducing factor (AIF).
Intracellular stresses such as increased oxidative stress, which may derive from the mitochondria themselves, activate the mitochondrial death pathway.
cytochrome c interacts with an adapter protein, apoptosis-activating factor (Apaf)-1
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
cyclophilin D (Cyp-D)
VDAC, voltage-dependent anion channel
ANT, adenine nucleotide translocase
The Bcl-2 family of proteins are key regulators of the mitochondrial death pathway.
----Bcl-2 Protein Family
Mediate both proapoptotic
and antiapoptotic regulation
BH1 (red), BH2 (orange), BH3 (green), and BH4 (yellow)
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.
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
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).
There are three well-characterized MAPK subfamilies that have already been mentioned, the ERKs, JNKs, and p38-MAPKs, all of which influence cell survival
Targets for Intervention
Initiation, regulation, and effector mechanisms offer potential molecular targets for antiapoptotic intervention.
BcL-2 family proteins
FasL: Fas ligand; cyt. C: cytochrome c; ARC: apoptosis repressor with a caspase recruitment domain; AIF:apoptosis-inducing factor.
Targeting the Proapoptotic Stimulus Acting on
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)