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Increasing levels of O‐linked N‐acetylglucosamine (O‐GlcNAc) on cardiac proteins during reperfusion improves recovery following ischemia/reperfusion and attenuates calpain‐mediated proteolysis
Author(s) -
Liu Jia,
Marchase Richard B,
Chatham John C
Publication year - 2007
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.21.6.a865
Subject(s) - calpain , proteolysis , ischemia , glucosamine , chemistry , reperfusion injury , myoglobin , cardiac function curve , medicine , endocrinology , biochemistry , enzyme , heart failure
We have previously shown that pre‐ischemic treatment with glucosamine improved cardiac functional recovery following ischemia/reperfusion (I/R) mediated, at least in part, via elevated protein O‐ GlcNAc levels. However, since pre‐ischemic treatment strategies are impractical for treatment of patients with myocardial ischemia, the goal of this study was to determine whether increasing protein O‐ GlcNAc levels only during reperfusion also improved recovery of function. Isolated perfused rat hearts were subjected to 20 min global, no flow ischemia followed by 60 min of reperfusion. Administration of glucosamine (10mM) or an inhibitor of O‐ GlcNAcase, O‐ (2‐acetamido ‐ 2‐deoxy‐d‐glucopyranosylidene) amino ‐ N‐phenylcarbamate (PUGNAc, 200 μM), during only the first 20 min of reperfusion significantly improved cardiac function, reduced troponin release and increased protein O‐ GlcNAc and ATP levels compared to untreated control. I/R resulted in significant loss of Ca 2+ /calmodulin‐dependent protein kinase II (CaMKII) and cleavage of α‐fodrin both of which are targets of the Ca 2+ ‐activated protease calpain. Both glucosamine and PUGNAc attenuated proteolysis of α‐fodrin and CaMKII and there was a significant correlation between function at the end or reperfusion and the amount of α‐fodrin cleavage. Thus, two independent strategies for increasing protein O‐ GlcNAc levels in the heart only during reperfusion significantly improved recovery and this was associated with attenuation of calcium‐mediated proteolysis. (Supported by NIH grants HL076165, and HL079364 ).