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O‐GlcNAc: Integration of Metabolic Signals and Cardioprotection
Author(s) -
Jones Steven Paul
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.lb16-c
Subject(s) - cardioprotection , cytoprotection , chemistry , signal transduction , myocyte , gsk 3 , glycogen , microbiology and biotechnology , endogeny , biochemistry , ischemia , medicine , oxidative stress , biology
We have recently discovered an endogenous mechanism of cytoprotection in the heart that involves the post‐translational modification of proteins with a metabolic signal. Although this stress‐responsive modification (beta‐O linkage of N‐acetylglucosamine, i.e. O‐GlcNAc) exerts profound salubrious effects on the myocardium, its mechanism remains untested. Here, we evaluated several potential cytoprotective pathways involved in O‐GlcNAc‐mediated protection. Isolated myocytes were subjected to three hours of hypoxia and followed over time during reoxygenation. Treatment with a novel compound (PUGNAc) that augments O‐GlcNAc levels preserved mitochondrial membrane potential, a proximal event in cell survival. As expected, PUGNAc enhanced O‐GlcNAc levels at baseline and were maintained throughout reoxygenation. Conversely, Vehicle treated myocytes exhibited a modest, but consistent time‐dependent loss of O‐GlcNAc levels during reoxygenation. Considering the role of glycogen synthase kinase‐3β (GSK‐3β) as important central signaling molecule in cardioprotection, we sought to identify a potential relationship between O‐GlcNAc levels and P‐GSK‐3β levels. Surprisingly, augmentation of O‐GlcNAc levels actually elevated levels of P‐GSK‐3β, contrary to the notion that the post‐translational modification by O‐GlcNAc and phosphate are absolutely reciprocal. These data provide unique insights into potential mechanisms of O‐GlcNAc mediated cardioprotection. Ongoing efforts are focused on identifying protein targets modified by O‐GlcNAc in the heart that are responsible for the cytoprotective effects following ischemia.