HAX-1 represses postmitochondrial caspase-9 activation and cell death during hypoxia-reoxygenation.

Adelicate balance exists between cell growth and cell death. In the context of the adult myocardium, inappropriate or inordinate cell loss through an apoptotic process, coupled with the limited regenerative ability of the heart to repair after injury, has been suggested to be a contributing factor to the decline in ventricular performance in patients with heart failure. The ability to prevent or modulate untimely or inordinate cardiac cell death after myocardial injury would be of significant therapeutic value in maintaining cardiac function. For this reason, there has been considerable interest in deciphering the signaling pathways and cellular factors that govern cell survival and cell death under normal and disease conditions. Apoptosis has received considerable attention in recent years by virtue of the events leading to cell death occurring through a highly ordered, genetically regulated process. This lends versatility for the design of novel therapies against cellular targets known to activate or repress cell death. Regulation of apoptosis in mammalian cells arises from the seminal discoveries of the ced-3, ced-4, and ced-9 genes in Caenorhabditis elegans. Mammalian counterparts to ced-3 and ced-4 have been cloned and identified. Ced-3 belongs to a large family of cellular cystine proteases, known collectively as caspases (for cysteinyl-aspartate–specific proteases) for their preferential ability to cleave cellular substrates after aspartic acid residues (reviewed previously1–3). The cleavage of caspase-specific substrates results in the biochemical destruction of the cell and phenotypic changes associated with apoptosis. To date, more than 14 caspases have been identified (reviewed previously2,3). Of these, caspase-2, -8, -9, and -10 are thought to be initiator caspases, whereas caspase-3, -6, and -7 are considered to be death effectors. Other caspases, including caspase-1, -4, -5, -11, -13, and -14, have been implicated in the inflammatory response.4,5 Caspase-12, which localizes to the endoplasmic reticulum (ER), may play a role in the ER stress response.6,7 Caspases exist as inactive zymogens and require proteolytic cleavage for full biological activity. Initiator caspases have a long prodomain that contains either a CARD (CAspase Recruitment Domain) (caspase-2 and -9) or a death effector domain (DED) (caspase-8 and -10). Unlike the death effector caspases, which are activated by simple caspase cleavage, the activation of the initiator caspases, such as caspase-9, is more complex, involving autocatalytic processing by induced proximity of caspase monomers.8 Homotypic or heterotypic interactions with the DED or CARD with adaptor proteins can also facilitate proteolytic activation of caspases.9–11 One paradigm for caspase activation follows a receptorregulated process, or “extrinsic pathway,” that includes death receptors, DR5, DR4, Fas, CD95, and tumor necrosis factor (TNF)receptors. In this model, binding of ligand to receptor promotes assembly of the death-inducing signaling complex (DISC),12 followed by recruitment of death domain (DD) and DED coupling proteins, which facilitates the activation of initiator caspases 8 and 10.8,13 The processing of upstream “initiator” caspases can sequentially activate prodeath factors, such as Bid, or more distal “death effector” caspases, such as caspase-3, -6, or -7.14 In addition to a receptor-based model for caspase activation, a mitochondrial-regulated or “intrinsic” pathway for caspase activation has recently been described. Mitochondrial defects leading to permeability transition pore (PTP) opening is considered a central component of the intrinsic mitochondrial death pathway.14–16 The PTP is presumed to be comprised in part by porin/voltage dependent anion channel and the adenine nucleotide translocase, as well as other outer and inner mitochondrial membrane proteins. The PTP opens in response to death signals. This results in mitochondrial swelling, generation of reactive oxygen species, and dissipation of m. Mitochondrial PTP opening has been reported during hypoxia, increased intracellular calcium, as well as oxidative stress injury.18 Furthermore, PTP opening is thought to trigger release of proapoptotic factors by mitochondria such as Smac (Second mitochondrial activator of caspases), cytochrome c,19 apoptosis-inducing factor (AIF), Htr2A/Omi, endonuclease G (Endo G), and other factors (reviewed previously20,21). Ostensibly, interaction of the CARD domain of pro– caspase-9 with the CARD domain of the ced-4 homolog, Apaf-1 (Apoptosis-activating factor-1), together with cytochrome c, form the apoptosome and in the presence of dATP result in the activation of caspase-922 (Figure). Once activated, caspase-9 is believed to facilitate the activation of death effector caspases 3, 6, and 7, resulting in the biochemical destruction of the cell. Endogenous inhibitors of the apoptosome include the inhibitor of apoptosis proteins (IAP-1, IAP-2) and X-linked inhibitor (XIAP), which are believed to avert apoptosis by inhibiting caspase-9.23 Moreover, several lines of investigation suggest a close association between the intrinsic death pathway and members of the Bcl-2 gene family.24 For example, life-promoting Bcl-2 family members typically prevent cell death by interfering with preor postmitochondrial events required for caspase activation, whereas death-promoting members such as Bax, The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From The Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Departments of Physiology, Pharmacology & Therapeutics, Faculty of Medicine University of Manitoba, Winnipeg, Canada. Correspondence to Dr Lorrie A. Kirshenbaum, Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Rm 3016, 351 Taché Ave, Winnipeg, Manitoba R2H 2A6, Canada. E-mail [email protected] (Circ Res. 2006;99:336-338.) © 2006 American Heart Association, Inc.