Inhibition of O-GlcNAcase in perfused rat hearts by NAG-thiazolines at the time of reperfusion is cardioprotective in an O-GlcNAc-dependent manner

Boglarka Laczy; Susan A Marsh; Charlye A Brocks; Istvan Wittmann; John C Chatham

doi:10.1152/ajpheart.00337.2010

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Inhibition of O-GlcNAcase in perfused rat hearts by NAG-thiazolines at the time of reperfusion is cardioprotective in an O-GlcNAc-dependent manner

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Inhibition of O-GlcNAcase in perfused rat hearts by NAG-thiazolines at the time of reperfusion is cardioprotective in an O-GlcNAc-dependent manner

Boglarka Laczy, Susan A Marsh, Charlye A Brocks, Istvan Wittmann and John C Chatham

American journal of physiology. Heart and circulatory physiology, Vol.299(5), pp.H1715-1727

11/2010

DOI: https://doi.org/10.1152/ajpheart.00337.2010

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https://hdl.handle.net/2376/111708

PMCID: PMC2993218

PMID: 20833964

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Abstract

beta-N-Acetylhexosaminidases - metabolism

Enzyme Inhibitors - pharmacology

Rats

Acetylglucosamine - pharmacology

Acetylglucosamine - therapeutic use

Male

beta-N-Acetylhexosaminidases - antagonists & inhibitors

Thiazoles - therapeutic use

Enzyme Inhibitors - therapeutic use

Rats, Sprague-Dawley

Acetylglucosamine - metabolism

Myocardial Reperfusion Injury - metabolism

Animals

Desmin - metabolism

Myocardium - metabolism

Acetylglucosamine - analogs & derivatives

Models, Animal

Thiazoles - pharmacology

Myocardial Reperfusion Injury - prevention & control

Acute increases in O-linked β-N-acetylglucosamine (O-GlcNAc) levels of cardiac proteins exert protective effects against ischemia-reperfusion (I/R) injury. One strategy to rapidly increase cellular O-GlcNAc levels is inhibition of O-GlcNAcase (OGA), which catalyzes O-GlcNAc removal. Here we tested the cardioprotective efficacy of two novel and highly selective OGA inhibitors, the NAG-thiazoline derivatives NAG-Bt and NAG-Ae. Isolated perfused rat hearts were subjected to 20 min global ischemia followed by 60 min reperfusion. At the time of reperfusion, hearts were assigned to the following four groups: 1) untreated control; 2) 50 μM NAG-Bt; 3) 100 μM NAG-Bt; or 4) 50 μM NAG-Ae. All treatment groups significantly increased total O-GlcNAc levels (P < 0.05 vs. control), and this was significantly correlated with improved contractile function and reduced cardiac troponin I release (P < 0.05). Immunohistochemistry of normoxic hearts showed intense nuclear O-GlcNAc staining and higher intensity at Z-lines with colocalization of O-GlcNAc and the Z-line proteins desmin and vinculin. After I/R, there was a marked loss of both cytosolic and nuclear O-GlcNAcylation and disruption of normal striated Z-line structures. OGA inhibition largely preserved structural integrity and attenuated the loss of O-GlcNAcylation; however, nuclear O-GlcNAc levels remained low. Immunoblot analysis confirmed ∼50% loss in both nuclear and cytosolic O-GlcNAcylation following I/R, which was significantly attenuated by OGA inhibition (P < 0.05). These data provide further support for the notion that increasing cardiac O-GlcNAc levels by inhibiting OGA may be a clinically relevant approach for ischemic cardioprotection, in part, by preserving the integrity of O-GlcNAc-associated Z-line protein structures.

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Title: Inhibition of O-GlcNAcase in perfused rat hearts by NAG-thiazolines at the time of reperfusion is cardioprotective in an O-GlcNAc-dependent manner
Creators: Boglarka Laczy - Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294-0007, USA
Susan A Marsh
Charlye A Brocks
Istvan Wittmann
John C Chatham
Publication Details: American journal of physiology. Heart and circulatory physiology, Vol.299(5), pp.H1715-1727
Academic Unit: Pharmaceutical Sciences, Department of
Publisher: United States
Grant note: HL-079364 / NHLBI NIH HHS HL-067464 / NHLBI NIH HHS
Identifiers: 99900547799901842
Language: English
Resource Type: Journal article