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

• Published in: The Journal of cell biology Vol. 171; no. 6; pp. 925 - 930
• Main Authors: Potts, Malia B, Vaughn, Allyson E, McDonough, Holly, Patterson, Cam, Deshmukh, Mohanish
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 19.12.2005; The Rockefeller University Press
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Apoptotic Protease-Activating Factor 1; Caspases - metabolism; Cells; Cells, Cultured; Cellular biology; Cytochromes; Cytochromes c - metabolism; Cytochromes c - pharmacology; Cytosol - metabolism; Fibroblasts; Gene expression; HeLa cells; Intracellular Signaling Peptides and Proteins - metabolism; Mice; Microinjections; Microscopy, Fluorescence; Myocardium; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - enzymology; Myocytes, Cardiac - metabolism; Neurons; Physiological regulation; Proteins - metabolism; Rats; Time Factors; Transfection; Ungulates; X-Linked Inhibitor of Apoptosis Protein - metabolism; X-Linked Inhibitor of Apoptosis Protein - pharmacology
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.200504082

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.