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Glutamine protects isolated rat heart from ischemia/reperfusion injury through the hexosamine biosynthesis pathway
Author(s) -
Liu Jia,
Marchase Richard B,
Chatham John C
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.20.4.a317-b
Subject(s) - glutamine , azaserine , glutamine amidotransferase , cardioprotection , chemistry , biochemistry , biosynthesis , reperfusion injury , pharmacology , ischemia , medicine , amino acid , enzyme
A number of reports have demonstrated that glutamine protects the heart from ischemia/reperfusion (I/R) injury; however, the mechanisms underlying this protection have yet to be fully elucidated. Glutamine: fructose‐6‐phosphate amidotransferase (GFAT) regulates the entry of glucose into the hexosamine biosynthesis pathway (HBP) and recent studies have shown that activation of this pathway is cardioprotective. Since glutamine is essential for GFAT activity the goal of this study was to determine whether the cardioprotective effects of glutamine was due to increased flux through the HBP and elevated levels of O ‐linked N‐acetyl‐glucosamine ( O ‐GlcNAc) on proteins. Hearts from male rats were isolated and perfused with Krebs‐Henseleit buffer containing 5mM glucose and global, no‐flow ischemia was induced for 20min followed by 60 min reperfusion.30 min pre‐treatment with 5 mM glutamine significantly improved functional recovery (RPP = 15.6±5.7% Vs. 59.4±6.1%; p<0.05) and decreased cardiac Troponin I release (25.4±3.0 Vs. 4.7±1.9; p<0.05) during reperfusion. This protection was associated with a significant increase in the levels of UDP‐GlcNAc, protein O‐GlcNAc and ATP. Pre‐treatment with 80μM azaserine, an inhibitor of GFAT, completely reversed the protection seen with glutamine and prevented the increase in UDP‐GlcNAc and protein O‐GlcNAc.O‐GlcNAc transferase (OGT) catalyzes the formation of O‐GlcNAc and inhibition of OGT with 5mM alloxan, also reversed the protection associated with glutamine. These data support the hypothesis that glutamine cardioprotection is due, at least in part, to enhanced flux through the HBP and increased protein O‐GlcNAc levels. This study was supported by NIH grant HL076165.