Myocardial creatine levels do not influence response to acute oxidative stress in isolated perfused heart
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...
| Principais autores: | , , , , , , |
|---|---|
| Formato: | Journal article |
| Idioma: | English |
| Publicado em: |
Public Library of Science
2014
|
| _version_ | 1826282876405022720 |
|---|---|
| author | Aksentijević, D Zervou, S Faller, K McAndrew, D Schneider, J Neubauer, S Lygate, C |
| author_facet | Aksentijević, D Zervou, S Faller, K McAndrew, D Schneider, J Neubauer, S Lygate, C |
| author_sort | Aksentijević, D |
| collection | OXFORD |
| description | 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 µM (30 min), or the anti-neoplastic drug doxorubicin 15 µM (100 min). Protein carbonylation, creatine kinase isoenzyme activities and phospho-PKCδ 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 wild-type 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. |
| first_indexed | 2024-03-07T00:50:27Z |
| format | Journal article |
| id | oxford-uuid:86367def-758e-4c11-a485-4a4d7d5c8f3d |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T00:50:27Z |
| publishDate | 2014 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | oxford-uuid:86367def-758e-4c11-a485-4a4d7d5c8f3d2022-03-26T22:02:28ZMyocardial creatine levels do not influence response to acute oxidative stress in isolated perfused heartJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:86367def-758e-4c11-a485-4a4d7d5c8f3dEnglishSymplectic Elements at OxfordPublic Library of Science2014Aksentijević, DZervou, SFaller, KMcAndrew, DSchneider, JNeubauer, SLygate, CBACKGROUND: 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 µM (30 min), or the anti-neoplastic drug doxorubicin 15 µM (100 min). Protein carbonylation, creatine kinase isoenzyme activities and phospho-PKCδ 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 wild-type 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. |
| spellingShingle | Aksentijević, D Zervou, S Faller, K McAndrew, D Schneider, J Neubauer, S Lygate, C Myocardial creatine levels do not influence response to acute oxidative stress in isolated perfused heart |
| title | Myocardial creatine levels do not influence response to acute oxidative stress in isolated perfused heart |
| title_full | Myocardial creatine levels do not influence response to acute oxidative stress in isolated perfused heart |
| title_fullStr | Myocardial creatine levels do not influence response to acute oxidative stress in isolated perfused heart |
| title_full_unstemmed | Myocardial creatine levels do not influence response to acute oxidative stress in isolated perfused heart |
| title_short | Myocardial creatine levels do not influence response to acute oxidative stress in isolated perfused heart |
| title_sort | myocardial creatine levels do not influence response to acute oxidative stress in isolated perfused heart |
| work_keys_str_mv | AT aksentijevicd myocardialcreatinelevelsdonotinfluenceresponsetoacuteoxidativestressinisolatedperfusedheart AT zervous myocardialcreatinelevelsdonotinfluenceresponsetoacuteoxidativestressinisolatedperfusedheart AT fallerk myocardialcreatinelevelsdonotinfluenceresponsetoacuteoxidativestressinisolatedperfusedheart AT mcandrewd myocardialcreatinelevelsdonotinfluenceresponsetoacuteoxidativestressinisolatedperfusedheart AT schneiderj myocardialcreatinelevelsdonotinfluenceresponsetoacuteoxidativestressinisolatedperfusedheart AT neubauers myocardialcreatinelevelsdonotinfluenceresponsetoacuteoxidativestressinisolatedperfusedheart AT lygatec myocardialcreatinelevelsdonotinfluenceresponsetoacuteoxidativestressinisolatedperfusedheart |