Role of the Fas/Fas-L pathway-mediated apoptosis in inflammatory heart diseases and vasculature diseases.

AN OVERVIEW ON CELL DEATH The focus of the reviews by Stoneman and Bennett and Henriques et al is cell death in the cardiovascular system. Specifically, these excellent reviews discuss in depth the involvement of the Fas/Fas-L pathway in apoptotic death of myocytes and vascular cells in cardiovascular and inflammatory heart diseases and potential therapeutic modalities for targeting this pathway as a means to attenuate the disease process. Cell death is a critical event in the cell cycle in animals and plants and is involved in numerous processes in health and disease, like embryonic development, immunological selection, heart failure, myocardial infarction, myocarditis, and atherosclerosis. Before addressing the reviews ahead, I will present a brief outline of the different death pathways of which apoptosis is a key member. Although the ultimate outcome is practically the same, cell demise, 3 distinct pathways may lead to this common fate: autophagy, necrosis, and apoptosis, which differ in their triggers, morphology, underlying mechanisms, and roles in life and death. Autophagy is involved in sequestration of cytosolic constituents, including proteins and organelles, in autophagosomes, which fuse with lysosomes to form autolysosomes. Although under normal or mildly stressful conditions in the myocardium autophagy degrades or recycles cytoplasmic components, for example long-lived proteins and organelles, autophagy is upregulated in a variety of disease states, such as heart failure and ischemia/reperfusion injury. Necrosis is caused by a significant cell injury, which abolishes the selectivity of the cell membrane and always constitutes a pathological condition. Morphologically, necrosis is characterized by swelling and explosion of the cell and is accompanied by mitochondrial dysfunction, adenosine triphosphate degradation, and release and activation of lysosomal enzymes. Furthermore, the necrotic cell contents are released into the environment causing inflammation by attracting various blood cells. While necrosis is a random process, often initiated by hostile environmental stimuli, the third death pathway—apoptosis—is a programmed cell death (often referred to as suicidal death) in which distinct, energydependent intracellular signaling pathways are activated. Apoptosis, which of the 3 pathways is the most complex/sophisticated and ubiquitous cell death, was initially recognized in 1972 by its distinctive morphology and was named after the Greek designation for leaves ‘‘falling off. ’’ As both reviews portray different aspects of the apoptotic pathway, this editorial describes the apoptotic process only briefly. Apoptosis occurs normally in countless situations and serves to eliminate unwanted or potentially harmful cells and cells that have outlived their usefulness. It is also a pathological event when cells are damaged beyond repair. One of the more specific features of apoptosis is protein hydrolysis involving the activation of several members of a family of cysteine proteases named caspases. Caspases (Cysteine ASPartyl proteASES) are unique proteases, which have a characteristic cysteine in their active enzymatic motif, and are able to cleave target proteins in a specific amino acid sequence but only after aspartate. Caspases are divided into 2 groups: initiators and executioners; among the initiator caspases are caspase-8, -9, -2, and -10, which are activated either by the mitochondrial pathway (caspase9) or by the death receptor pathway (caspase-8 and to a lesser extent caspase-10), and consequently activate the executioner caspases. The executioner caspases (such as caspase-3,