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(Circulation Research. 2009;104:41.)
© 2009 American Heart Association, Inc.

Molecular Medicine

Unique Hexosaminidase Reduces Metabolic Survival Signal and Sensitizes Cardiac Myocytes to Hypoxia/Reoxygenation Injury

Gladys A. Ngoh, Heberty T. Facundo, Tariq Hamid, Wolfgang Dillmann, Natasha E. Zachara, Steven P. Jones

From the Institute of Molecular Cardiology (G.A.N., H.T.F., T.H., S.P.J.) and Department of Physiology and Biophysics (G.A.N., S.P.J.), University of Louisville, Ky; Division of Endocrinology and Metabolism (W.D.), Department of Medicine, University of California; and Department of Biological Chemistry (N.E.Z.), Johns Hopkins University School of Medicine, Baltimore, Md.

Correspondence to Steven P. Jones, PhD, Institute of Molecular Cardiology, Department of Medicine, 580 S Preston St, Baxter II–404C, Louisville, KY 40202. E-mail Steven.P.Jones{at}Louisville.edu

Metabolic signaling through the posttranslational linkage of N-acetylglucosamine (O-GlcNAc) to cellular proteins represents a unique signaling paradigm operative during lethal cellular stress and a pathway that 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 (ie, O-GlcNAcase) from proteins. We used pharmacological 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 posthypoxic cell death. Conversely, short interfering RNA directed against, or pharmacological inhibition of, O-GlcNAcase significantly augmented O-GlcNAc levels and reduced posthypoxic cell death. On the mechanistic front, we evaluated posthypoxic mitochondrial membrane potential and found that repression of O-GlcNAcase activity improves, whereas augmentation impairs, mitochondrial membrane potential recovery. Similar beneficial effects on posthypoxic 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 (ie, voltage-dependent anion channel, adenine nucleotide translocase, cyclophilin D). The present results provide definitive evidence that O-GlcNAcase antagonizes posthypoxic cardiac myocyte survival. Moreover, such results support a renewed approach to the contribution of metabolism and metabolic signaling to the determination of cell fate.

Key Words: O-GlcNAc • mitochondria • hypoxia • cell death • posttranslational modification

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