Increasing protein O‐GlcNAc levels by inhibition of O‐GlcNAcase improves cardiac function following trauma hemorrhage and resuscitation in rat

Abstract

Our previous studies have shown that administration of glucosamine during resuscitation following trauma-hemorrhage (T-H) improved cardiac output and organ perfusion. Glucosamine administration also increased levels of N-acetyl-glucosamine (O-GlcNAc) on proteins in heart and brain. An alternative means of increasing O-GlcNAc levels is by inhibition of O-GlcNAcase, which catalyzes removal of GlcNAc from proteins with O-(2-acetamido-2-deoxy-d-glucopyranosylidene) amino-N-phenylcarbamate (PUGNAc). The goal of this study therefore, was to determine whether PUGNAc administration following T-H also improves recovery following T-H. Fasted male rats were bled to and maintained at a mean arterial blood pressure of 40 mmHg for 90 min followed by fluid resuscitation. Administration of 300μ l of 20mM PUGNAc 30 min after the onset of resuscitation significantly improved cardiac output compared to the vehicle controls (14±2 vs. 26±2 mls/min/100g body wt; p<0.05); decreased total peripheral resistance (6.2±0.9 vs. 3.7±3 mmHg/mls/min/100g body wt; p<0.05), and increased perfusion of critical organs systems, including kidney, liver and brain, determined 2hrs after the end of resuscitation. PUGNAc also attenuated the T-H induced increase in plasma IL-6 levels (864±112 Vs 392±188 pmols/ml; p<0.05). PUGNAc also significantly increased O-GlcNAc levels in heart, liver and skeletal muscle but not brain. Thus, PUGNAc, like glucosamine, improves cardiac function and organ perfusion and reduced the level of circulating IL-6 following T-H. The similar effects of glucosamine and PUGNAc suggest that this protection is mediated via increased protein O-GlcNAc levels. Supported by NIH grants RO1 HL076165-01(RBM) and R37 GM39519 (IHC).