Myocardial creatine levels do not influence response to acute oxidative stress in isolated perfused heart

Zazueta, C., Aksentijević, D., Zervou, S., Faller, K. M.E., McAndrew, D. J., Schneider, J. E., Neubauer, S. and Lygate, C. A. (2014) Myocardial creatine levels do not influence response to acute oxidative stress in isolated perfused heart. PLoS ONE, 9(10), e109021. (doi: 10.1371/journal.pone.0109021) (PMID:25272153) (PMCID:PMC4182806)

Abstract

Background: Multiple studies suggest creatine mediates anti-oxidant activity in addition to its established role in cellular energy metabolism. The functional significance for the heart has yet to be established, but antioxidant activity could contribute to the cardioprotective effect of creatine in ischaemia/reperfusion injury. Objectives: To determine whether intracellular creatine levels influence responses to acute reactive oxygen species (ROS) exposure in the intact beating heart. We hypothesised that mice with elevated creatine due to over-expression of the creatine transporter (CrT-OE) would be relatively protected, while mice with creatine-deficiency (GAMT KO) would fare worse. Methods and Results: CrT-OE mice were pre-selected for creatine levels 20–100% above wild-type using in vivo 1 H– MRS. Hearts were perfused in isovolumic Langendorff mode and cardiac function monitored throughout. After 20 min equilibration, hearts were perfused with either H2O2 0.5 mM (30 min), or the anti-neoplastic drug doxorubicin 15 mM (100 min). Protein carbonylation, creatine kinase isoenzyme activities and phospho-PKCd expression were quantified in perfused hearts as markers of oxidative damage and apoptotic signalling. Wild-type hearts responded to ROS challenge with a profound decline in contractile function that was ameliorated by co-administration of catalase or dexrazoxane as positive controls. In contrast, the functional deterioration in CrT-OE and GAMT KO hearts was indistinguishable from wildtype controls, as was the extent of oxidative damage and apoptosis. Exogenous creatine supplementation also failed to protect hearts from doxorubicin-induced dysfunction. Conclusions: Intracellular creatine levels do not influence the response to acute ROS challenge in the intact beating heart, arguing against creatine exerting (patho-)physiologically relevant anti-oxidant activity.

• Item Type: Articles
• Additional Information: This work was supported by the British Heart Foundation Programme Grant RG/13/8/30266 to SN and CAL. JES is BHF Senior Basic Science Research Fellow (FS/11/50/29038). We would also like to acknowledge Wellcome Trust Core Award Grant 075491/Z/04. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Faller, Ms Kiterie
• Authors: Zazueta, C., Aksentijević, D., Zervou, S., Faller, K. M.E., McAndrew, D. J., Schneider, J. E., Neubauer, S., and Lygate, C. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine
• Journal Name: PLoS ONE
• Publisher: Public Library of Science
• ISSN: 1932-6203
• ISSN (Online): 1932-6203
• Copyright Holders: Copyright © 2014 Aksentijević et al.
• First Published: First published in PLoS ONE 9(10): e109021
• Publisher Policy: Reproduced under a Creative Commons License