Selective protein kinase C inhibition switches time-dependent glucose cardiotoxicity to cardioprotection

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-.

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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
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