Unique hexosaminidase reduces metabolic survival signal and sensitizes cardiac myocytes to hypoxia/reoxygenation injury.
Unique hexosaminidase reduces metabolic survival signal and sensitizes cardiac myocytes to hypoxia/reoxygenation injury.
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DOI：
10.1161/circresaha.108.189431
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发表时间：
2009-01-02
影响因子：
20.1
通讯作者：
Jones SP
中科院分区：
文献类型：
--
作者：
Ngoh GA;Facundo HT;Hamid T;Dillmann W;Zachara NE;Jones SP
Metabolic signaling through the post-translational linkage of N-acetylglucosamine (O-GlcNAc) to cellular proteins represents a unique signaling paradigm operative during lethal cellular stress, and, a pathway we and others have recently shown to exert cytoprotective effects in vitro and in vivo. Accordingly, the present work addresses the contribution of the hexosaminidase responsible for removing O-GlcNAc (i.e. O-GlcNAcase) from proteins. We used pharmacologic inhibition, viral overexpression, and RNA interference of O-GlcNAcase in isolated cardiac myocytes to establish its role during acute hypoxia-reoxygenation. Elevated O-GlcNAcase expression significantly reduced O-GlcNAc levels and augmented post-hypoxic cell death. Conversely, short interfering RNA directed against, or pharmacologic inhibition of, O-GlcNAcase significantly augmented O-GlcNAc levels and reduced post-hypoxic cell death. On the mechanistic front, we evaluated post-hypoxic mitochondrial membrane potential and found that repression of O-GlcNAcase activity improves, while augmentation impairs, mitochondrial membrane potential recovery. Similar beneficial effects on post-hypoxic calcium overload were also evident. Such changes were evident without significant alteration in expression of the major putative components of the mitochondrial permeability transition pore (i.e. VDAC, ANT, CypD). The present results provide definitive evidence that O-GlcNAcase antagonizes post-hypoxic cardiac myocyte survival. Moreover, such results support a renewed approach to the contribution of metabolism and metabolic signaling to the determination of cell fate.
