We describe the isolation and characterization of a new apaf-1-interacting protein (APIP) as a negative regulator of ischemic injury. APIP is highly expressed in skeletal muscle and heart and binds to the CARD of Apaf-1 in competition with caspase-9. Exogenous APIP inhibits cytochrome c-induced activation of caspase-3 and caspase-9, and suppresses cell death triggered by mitochondrial apoptotic stimuli through inhibiting the downstream activity of cytochrome c released from mitochondria. Conversely, reduction of APIP expression potentiates mitochondrial apoptosis. APIP expression is highly induced in mouse muscle affected by ischemia produced by interruption of the artery in the hindlimb and in C2C12 myotubes created by hypoxia in vitro, and the blockade of APIP up-regulation results in TUNELpositive ischemic damage. Furthermore, forced expression of APIP suppresses ischemia/hypoxia-induced death of skeletal muscle cells. Taken together, these results suggest that APIP functions to inhibit muscle ischemic damage by binding to Apaf-1 in the Apaf-1/ caspase-9 apoptosis pathway.

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Numerous studies have established a link between autophagy and aging; however, the relationship has not been clearly defined. Aging is a very complex process caused by the accumulation of various factors due to the gradual failure of cellular maintenance. Recent studies have shown that autophagy reduces the stress responses induced by starvation, reactive oxygen species, and the accumulation of intracellular proteins and organelles through cytoprotection, clearance of damaged mitochondria, and lysosomal degradation. Here, we summarize our current understanding of the relationship between autophagy and the aging process.

The ischemic death of cardiomyocytes is associated in heart disease and heart failure. However, the molecular mechanism underlying ischemic cell death is not well defined. To examine the function of apoptosis repressor with a caspase recruitment domain (ARC) in the ischemic/hypoxic damage of cardiomyocytes, we generated cardio-specific ARC transgenic mice using a mouse ␣-myosin heavy chain promoter. Compared with the control, the hearts of ARC transgenic mice showed a 3-fold overexpression of ARC. Langendoff preparation showed that the hearts isolated from ARC transgenic mice exhibited improved recovery of contractile performance during reperfusion. The cardiomyocytes cultured from neonatal ARC transgenic mice were significantly resistant to hypoxic cell death. Furthermore, the ARC C-terminal calcium-binding domain was as potent to protect cardiomyocytes from hypoxic cell death as ARC. Genome-wide RNA expression profiling uncovered a list of genes whose expression was changed (>2-fold) in ARC transgenic mice. Among them, expressional regulation of developmentally regulated RNA-binding protein 1 (Drbp1) or the dimethylglycine dehydrogenase precursor (pMe 2 GlyDH) affected hypoxic death of cardiomyocytes. These results suggest that ARC may protect cardiomyocytes from hypoxic cell death by regulating its downstream, Drbp1 and pMe 2 GlyDH, shedding new insights into the protection of heart from hypoxic damages.Programmed cell death, or apoptosis, is an evolutionarily conserved process that plays a critical role in embryonic development and adult tissue homeostasis. In humans and mice, dysregulated apoptosis has been implicated in the pathogenesis of cancer and in autoimmune, cardiovascular, and neurodegenerative diseases (1). Recently, apoptosis of cardiomyocytes has been recognized as a cellular mechanism of ischemic injury in the heart. Furthermore, a large body of research has focused on identifying the signaling molecules that might protect the myocardium from ischemic damage (2). For example, signaling molecules enhance apoptosis of cardiomyocytes, such as p38, c-Jun N-terminal kinase, tumor necrosis factor-␣, p53, ␤-adrenergic receptors, and nitric oxide (2-4). In contrast, other signaling pathways have been demonstrated to protect the heart from apoptosis, such as cardiotrophin-1 through the gp130 receptor, p38␤, insulin-like growth factor-1, Akt/protein kinase B, protein kinase C, and extracellular signal-regulated kinase 1/2 (2, 3, 5-9). Thus, an increased understanding of the signaling pathways that are regulated during ischemia/reperfusion is important for the development of effective therapies (10).ARC 3 (apoptosis repressor with CARD) is a caspase recruitment domain (CARD) protein that is expressed almost exclusively in long-lived tissues, such as heart, skeletal muscles, and brain. ARC selectively interacts with the initiator caspases-2 and -8, and significantly attenuates death receptor-induced apoptosis dependent on the activation of these caspases (11). In the H9c2 cell line, ectopic expression of A...