Selective protein kinase C inhibition switches time-dependent glucose cardiotoxicity to cardioprotection
Squire, Iain
Squire, Iain
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 ex vivo 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 KATP channel activation, improved contractile and Ca2+ 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.
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Date
2022-09-07
Type
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Brennan, S., Esposito, S., Abdelaziz, M. I. M., Martin, C. A., Makwana, S., Sims, M. W., Squire, I. B., Sharma, P., Chadwick, A. E., & Rainbow, R. D. (2022). Selective protein kinase C inhibition switches time-dependent glucose cardiotoxicity to cardioprotection. Frontiers in cardiovascular medicine, 9, 997013. https://doi.org/10.3389/fcvm.2022.997013