Recent evidence reveals that IR-induced myocardial cell death is not limited to necrosis but also includes apoptotic cell death (Kloner and Jennings, 2001; McCully et al., 2004). Apoptosis can be generally defined as programmed cell suicide utilizing specific mechanisms of initiation and execution in an energy dependent manner. Morphologically, apoptosis is characterized by nuclear chromatin condensation, loss of nuclear and cellular volume and finally blebbing of the nuclear and cellular membranes (Kloner and Jennings, 2001). Thus, apoptotic cell death is pathologically different from necrosis in that the former is a self-destructive response to unfavorable cellular conditions while the latter involves cell death via an external stimulus and cell rupture (Kloner and Jennings, 2001). There are numerous internal (i.e. noxious cellular environment) and external (i.e. cell death receptor stimulation) stimuli responsible for pathologic apoptosis. Activation of apoptotic death receptors on the sarcolemma includes activation multiple signaling pathways including NFKB, JNK and FADD. Alternately, internal mediators of apoptosis are inevitably mitochondrion-dependent resulting in an apoptotic signaling cascade through release of either cytochrome c or apoptosis inducing factor (AIF) from the mitochondrion (Haunstetter and Izumo, 2001). Importantly, cell death receptor and mitochondrial inducers of myocardial apoptosis result in activation of cysteine-aspartate dependent proteases, called caspases. Downstream caspase activation leading to apoptosis ultimately necessitates activation of caspase-3 as the final mechanism of apoptosis induction. Once activated, caspase-3 cleaves the DNA repair enzyme poly (ADP)-ribosylating protein (PARP) resulting in over activation. Once PARP is over activated, cellular energy stores are further depleted and apoptosis is initiated.
With respect to internal stimuli for myocardial apoptosis, growing evidence indicates that IR-induced necrotic and apoptotic forms of cell death occur in tandem and involve similar stimuli such as oxidative stress and Ca2+ overload (Fig. 8.2) (Kumar and Jugdutt, 2003). Since cardiac myocytes do not contain satellite cells and are incapable of cell division, prevention of IR-induced cell death is critical to the preservation of cardiac function following IR events. The next two sections will overview various aspects of free radical and calcium-mediated processes as mechanisms related to IR-induced myocardial injury and death.
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