Abstract
The AKT (protein kinase B, PKB) family has been shown to participate in diverse cellular processes, including apoptosis. Previous studies demonstrated that protein kinase B2 (AKT2−/−) mice heart was sensitized to apoptosis in response to ischemic injury. However, little is known about the mechanism and apoptotic signaling pathway. Here, we show that AKT2 inhibition does not affect the development of cardiomyocytes but increases cell death during cardiomyocyte ischemia. Caspase-dependent apoptosis of both the extrinsic and intrinsic pathway was inactivated in cardiomyocytes with AKT2 inhibition during ischemia, while significant mitochondrial disruption was observed as well as intracytosolic translocation of cytochrome C (Cyto C) together with apoptosis-inducing factor (AIF) and endonuclease G (EndoG), both of which are proven to conduct DNA degradation in a range of cell death stimuli. Therefore, mitochondria-dependent cell death was investigated and the results suggested that AIF and EndoG nucleus translocation causes cardiomyocyte DNA degradation during ischemia when AKT2 is blocked. These data are the first to show a previous unrecognized function and mechanism of AKT2 in regulating cardiomyocyte survival during ischemia by inducing a unique mitochondrial-dependent DNA degradation pathway when it is inhibited.
Highlights
Apoptosis is defined as programmed cell death (PCD), which is executed by a family of cysteinyl aspartate proteinases known as caspases [1]
Our results provide the evidence that apoptosis-inducing factor (AIF) and endonuclease G (EndoG) are two important factors involved in the regulation of caspase-independent cell death induced by ischemia-mediated cardiomyocte injury when AKT2 is inhibited
In order to investigate the role of AKT2 in the myocyte during ischemia, we initially compared apop2t.o1s. iAs-KrTe2laItnehdibgiteionneIsnadnucdesoEblseveartvioendosflAigphopttionticcrGeaensee EoxfpgreesnsieosniinnvMolyvoecadrdiinummwitiothcohuotnAdffreicatiln-dgependent apopMtoysoiscyitne NDeRvCeloMpms etnretated with a specific AKT2 inhibitor (Figure 1A, left panel)
Summary
Apoptosis is defined as programmed cell death (PCD), which is executed by a family of cysteinyl aspartate proteinases known as caspases [1]. Caspases belong to a family of highly conserved aspartate-specific cysteine proteases that are expressed as inactive zymogens in most animal cells and serve as the central executioners of apoptosis [2]. When activated, these enzymes cleave their protein substrates on the carboxy-terminal side of an aspartate residue [3]. An alternative pathway (the intrinsic pathway) involves the activation of caspase-9, which relies on the release of cytochrome c (Cyto C) and other mitochondrial proteins in the cytoplasm, and this process is controlled by B-cell lymphoma-2 (Bcl-2) family proteins [4]. Caspase-3 cleaves poly (ADP-ribose) polymerase (PARP), which decreases its DNA repair activity and leads to apoptotic cell death [5]
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