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Apoptosis pathway. Two distinct, but not mutually exclusive, pathways of apoptotic cell death have been well desribed: extrinsic and intrinsic pathways. In
the extrinsic pathway, soluble or cell surface death ligands, such as TNF-α and Fas ligand, bind to the corresponding death receptors inducing activation of
upstream caspases, such as caspase-8, followed by activation of downstream effector caspases. In the intrinsic pathway, cytochrome c is released from
mitochondria into the cytoplasm, often initiated by stress stimuli such as ischemia, oxidative stress, genotoxic stress, and calcium excess. These stimuli
activate BH3-only family members and inhibit the prosurvival BCL-2-like proteins. Cytoplasmic cytochrome c in presence of dATP/ATP binds Apaf-1 to
activate caspase-9 and subsequently downstream effector caspases. Once activated, the effector caspases fragment intracellular proteins resulting in the
Source: MOLECULAR AND CELLULAR BIOLOGY OF THE HEART, Hurst's The Heart, 14e
orderly destruction of the cell. The effector caspases also activate DNAses and lead to fragmentation of nuclear DNA.226 The death receptor and
Fuster
Harrington
Narula
J, Eapen
ZJ. Hurst's cThe
Heart,through
14e; 2017
Availablewith
at: http://mhmedical.com/
Accessed:
AugustBax
10,
mitochondrialCitation:
pathways
are V,
linked
by Bid,RA,
which
stimulates
cytochrome
release
interactions
the proapoptotic Bcl-family
members,
2017
227
228
and/or Bak. The antiapoptotic Bcl-family members, Bcl-2 and Bcl-xL inhibit cell death by competing with Bax and Bak. When apoptosis is induced, in
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McGraw-Hill
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addition to cytochrome
SMAC
is also released
from
the mitochondria
that binds to XIAP precluding its inhibition of caspases. APAF1, apoptotic
protease-activating factor 1; SMAC, second mitochondria-derived activator of caspases; tBID, truncated form of BID; TNF, tumor necrosis factor; XIAP, X-