Cell death in the pathogenesis and progression of heart failure
Heart Fail Rev
Cell death in the pathogenesis and progression of heart failure
Jose´ Mar´ın-Garc´ıa 0 1
0 The Molecular Cardiology and Neuromuscular Institute , 75 Raritan Avenue, Suite 225, Highland Park, NJ 08904 , USA
1 & Jose ́ Mar ́ın-Garc ́ıa
-
During evolution, all multicellular organisms develop the
highly complex and interconnected processes of cell death.
Initially thought to be an accidental uncontrolled
development, during the past two decades a clear and
comprehensive view has emerged on the many aspects of cell
death, which are genetically programmed and therefore
tightly regulated. Three major cell death modalities,
apoptosis, necrosis and autophagy (Fig. 1), occur in
cardiomyocytes, and both gradual and acute cell death are
features of the cardiac pathophysiology, including
ischemia/reperfusion (I/R), myocardial infarction (MI) and
progressive heart failure (HF).
The term ‘apoptosis’ (from ancient Greek word
describing ‘falling leaves’) introduced in 1972 define a
programmed cell death process distinct from ‘necrosis,’
which was initially considered as a purely accidental and
passive type of cell death [
1
]. In apoptosis, the plasma
membrane maintains its integrity until the late stages of the
process, while in necrosis the plasma membrane rapture,
swelling of organelles and loss of intracellular contents are
early events [
2, 3
].
Other morphological characteristics of apoptotic cell
death include cell rounding-up, reduction in cellular
volume (pyknosis), chromatin condensation, nuclear
fragmentation (karyorrhexis) and plasma membrane blebbing.
A biochemical hallmark of apoptosis is activation of two
groups of proteins, caspases (cysteinyl aspartyl proteases),
and members of the Bcl2 extended family.
The intrinsic or mitochondrial pathway and the extrinsic
or death receptor pathway are two distinct but interlinked
pathways which mediate apoptosis. The intrinsic or
mitochondrial apoptotic pathway is induced by various stress
stimuli, including growth factors deprivation, oxidative
stress (OS), genotoxic stress, hypoxia and various toxins. In
response to these signals, the members of the Bcl-2 family
are recruited to mitochondria and sarcoplasmic reticulum
(SR), triggering release of apoptotic proteins from the
former and release of Ca2? from the latter. The extrinsic
apoptotic pathway also known as the death receptor
pathway is initiated by the binding of death ligands, such as
FasL, tumor necrosis factor (TNF) or TRAIL, to their
cognate cell surface death domain-containing receptors,
known as death receptors [
4, 5
], which are members of the
large TNF receptor family characterized by the presence of
conserved intracellular death domains (DD), which are
essential for the initiation of the apoptotic response [6].
Chronic cardiac remodeling and transition to overt HF
have been associated with modestly increased apoptosis [
7,
8
], although the actual burden of chronic cell loss
attributable to apoptosis is not clear. Indeed, measures of
actual rates are highly variable and depend on the species,
type of injury, timing, location and method of assessment.
When viewed in absolute terms, the rate of apoptosis is
quite low [9]; however, when the relatively low rates are
viewed in the context of months or years, it is entirely
plausible that the apoptotic burden could be substantial.
Unfortunately, the timing of the apoptotic process is not
well defined and the assessment of the true rates and their
consequences is still quite limited.
Necrosis (from the Greek word ‘necros’ for corpse) is
characterized morphologically by cell and organelle
swelling (oncosis), early plasma membrane rapture and
resultant loss of intracellular contents (Fig. 1) [
10, 11
]. In
contrast to apoptosis, this cell death modality has been
considered a merely accidental uncontrolled process, but
growing evidence suggests that many aspects of necrosis
are programmed and tightly regulated. Investigators have
proposed that ‘necroptosis’ describes regulated necrotic
cell death [
4, 12, 13
] with numerous interlinked pathways
implicated in necrosis; however, the precise molecular
mechanisms of this process is not yet known.
Autophagic cell death or ‘macroautophagy,’ herein
referred to as ‘autophagy’ (from the Greek ‘phagy’—to eat,
and ‘auto’—oneself), is a tightly orchestrated stress-induced
pathway, which involves lysosome-mediated degradation of
cytosolic components and organelles [
4, 14–18
].
Morphologically, autophagy is characterized by massive formation
of single- or double-membrane lysosomal-derived vesicles,
which sequester degenerating cytoplasmic particles,
organelles and protein aggregates (Fig. 1). This evolutionary
conserved catabolic pathway plays an essential role during
mammalian development and differentiation [
19, 20
].
Autophagy is usually induced under various stress
conditions, including starvation, OS, I/R and pathogen infections,
and helps organisms to fight against degenerative, (...truncated)