Brennan, Sean, Esposito, Simona, Abdelaziz, Muhammad IM, Martin, Christopher AA, Makwana, Samir, Sims, Mark WW, Squire, Iain BB, Sharma, Parveen 
ORCID: 0000-0002-5534-2417, Chadwick, Amy EE ORCID: 0000-0002-7399-8655 and Rainbow, Richard D ORCID: 0000-0002-0532-1992
(2022)
Selective protein kinase C inhibition switches time-dependent glucose cardiotoxicity to cardioprotection.
FRONTIERS IN CARDIOVASCULAR MEDICINE, 9.
997013-.
Abstract
Hyperglycaemia at the time of myocardial infarction has an adverse effect on prognosis irrespective of a prior diagnosis of diabetes, suggesting glucose is the damaging factor. In <i>ex vivo</i> models of ischaemia, we demonstrated that deleterious effects of acutely elevated glucose are PKCα/β-dependent, and providing PKCα/β are inhibited, elevated glucose confers cardioprotection. Short pre-treatments with high glucose were used to investigate time-dependent glucose cardiotoxicity, with PKCα/β inhibition investigated as a potential mechanism to reverse the toxicity. Freshly isolated non-diabetic rat cardiomyocytes were exposed to elevated glucose to investigate the time-dependence toxic effects. High glucose challenge for >7.5 min was cardiotoxic, proarrhythmic and lead to contractile failure, whilst cardiomyocytes exposed to metabolic inhibition following 5-min high glucose, displayed a time-dependent protection lasting ∼15 min. This protection was further enhanced with PKCα/β inhibition. Cardioprotection was measured as a delay in contractile failure and K<sub>ATP</sub> channel activation, improved contractile and Ca<sup>2+</sup> transient recovery and increased cell survival. Finally, the effects of pre-ischaemic treatment with high glucose in a whole-heart coronary ligation protocol, where protection was evident with PKCα/β inhibition. Selective PKCα/β inhibition enhances protection suggesting glycaemic control with PKC inhibition as a potential cardioprotective therapeutics in myocardial infarction and elective cardiac surgery.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | glucose, cardiotoxicity, cardioprotection, hyperglycaemia, protein kinase C (PKC), time-dependent |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 26 Sep 2022 10:11 |
| Last Modified: | 18 Jan 2023 20:41 |
| DOI: | 10.3389/fcvm.2022.997013 |
| Open Access URL: | https://www.frontiersin.org/articles/10.3389/fcvm.... |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3165008 |
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