Reduced Apaf-1 levels in cardiomyocytes engage strict regulation of apoptosis by endogenous XIAP

Abstract

Overexpression studies have identified X-linked inhibitor of apoptosis protein (XIAP) as a potent inhibitor of caspases. However, the exact function of endogenous XIAP in regulating mammalian apoptosis is less clear. Endogenous XIAP strictly regulates cytochrome c–dependent caspase activation in sympathetic neurons but not in many mitotic cells. We report that postmitotic cardiomyocytes, unlike fibroblasts, are remarkably resistant to cytosolic microinjection of cytochrome c. The cardiomyocyte resistance to cytochrome c is mediated by endogenous XIAP, as XIAP-deficient cardiomyocytes die rapidly with cytosolic cytochrome c alone. Importantly, we found that cardiomyocytes, like neurons, have markedly reduced Apaf-1 levels and that this decrease in Apaf-1 is directly linked to the tight regulation of caspase activation by XIAP. These data identify an important function of XIAP in cardiomyocytes and point to a striking similarity in the regulation of apoptosis in postmitotic cells.

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

“…In contrast, the likelihood of MOMP induction following apoptosis stimuli seems to be unaffected by differentiation, or even higher than in undifferentiated cells [40,46,48]. Moreover, as also outline above, MOMP may be induced by elevated FAS signaling after DOX.…”

“…As such example, the studies of Potts [46] and Konorev [40] agreed that post-MOMP apoptosis is markedly reduced upon cell maturation, but attributed this effect to different protein regulation patterns. We therefore propose computational signal transduction models to investigate the effect of how combined changes in protein expression levels translate to cardiomyocyte vulnerability.…”

“…Interestingly, this protection was ablated by the XIAP-antagonist SMAC highlighting the balance of pro-and anti-apoptotic proteins in the post-MOMP pathway as decisive for this cardiomyocyte protection [46,47]. From their biochemical study, a positive correlation between differentiation status and decreased apoptosis likelihood in response to DOX is hence expected.…”

Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

“…ER, endoplasmic reticulum; GAB1, GRB2-associated binding protein 1; GRB2, growth factor receptorbound protein 2; NRG1, neuregulin 1; PIP 3 , phosphatidylinositol trisphosphate; SOS, son of sevenless. Unlike most tissues, neurons and cardiomyocytes are relatively resistant to apoptosis induced by cytochrome c release and caspase activation, possibly owing to increased expression of X-linked inhibitor of apoptosis (XIAP) and decreased expression of apoptotic protease activating factor 1 (APAF1) 38 . Consequently, antibodymediated inhibition of ERBB2 might regulate mitochondrial integrity through the BCL-X proteins, leading to ATP depletion and contractile dysfunction without profound changes in cardiomyocyte ultrastructure.…”

Variations in the protein level of Omi/HtrA2 in the heart of aged rats may contribute to the increased susceptibility of cardiomyocytes to ischemia/reperfusion injury and cell death

“…X-linked inhibitor of apoptosis protein (XIAP) is the best characterized and most potent endogenous regulators of apoptotic cell death in mammals (Holcik et al 2001). Many results revealed that it was a major inhibitor of apoptosis in cardiomyocytes (Potts et al 2005;Souktani et al 2009). Our primary results found decreased cardiac expression of XIAP in aging rats, and Li et al found a downregulated XIAP expression in aging transgenic mice hearts (Li and Ren 2007).…”