An alternative view of apoptosis in heart development and disease

Although the involvement of caspases in cardiomyocyte death is widely accepted [reviewed in1], increasing experimental evidence suggests that caspase activation is not relevant for post-mitotic cardiomyocyte cell death.2–7 Controversy also exists as to the mechanisms conferring cardioprotection by caspase inhibitors, which could be unrelated to apoptosis or target non-myocardial cells.8–11 In addition, the genes controlling the caspase-dependent death pathway are silenced during early post-natal development.7,12 Finally, the major role of death receptors and the Bcl-2-related proteins in the myocardium is probably to control differentiation, adaptation to stress and mitochondrial integrity. In light of these findings, we propose here an alternative explanation of the role of canonical apoptosis regulators in the control of cardiomyocyte life and death.Cell death implying apoptotic-like DNA damage occurs during embryonic heart development.13–15 Experiments using caspase inhibitors suggest that caspase-dependent cell death occurs in the cardiac regions submitted to important morphological changes, such as the ventriculoarterial connections, the atrioventricular cushions, and the conduction tissue.16–18 Therefore, caspase activation is likely assuring the proper formation of the cardiac cavities and the correct docking of the arteries to the ventricles during development. Later, the caspase-dependent death machinery is repressed during cardiomyocyte terminal differentiation,7,12 as it has been described in retinal neurons.19Many reports have demonstrated that mitochondrial damage precedes post-mitotic cardiomyocyte cell death and have suggested the involvement of caspases20 yet the engagement of these proteases downstream of mitochondrial damage is still debated [e.g. 4 vs. 21]. The Bcl-2 family controls mitochondrial events leading to caspase activation by regulating outer mitochondrial membrane permeabilization. However, mitochondrial damage also hinders aerobic metabolism and alters cellular Ca2+ homeostasis. Thus, Bcl-2 and Bcl-XL-dependent cardioprotection could be achieved by maintaining …