Cell death in the pathogenesis and progression of heart failure

Heart Failure Reviews, Feb 2016

José Marín-García

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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)


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José Marín-García. Cell death in the pathogenesis and progression of heart failure, Heart Failure Reviews, 2016, pp. 117-121, Volume 21, Issue 2, DOI: 10.1007/s10741-016-9538-7