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A novel form of glycolytic metabolism‐dependent cardioprotection revealed by PKCα and β inhibition

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journal contribution
posted on 2019-07-08, 14:51 authored by S Brennan, S Chen, S Makwana, C Martin, M Sims, A Alonazi, J Willets, I Squire, R Rainbow
Background Hyperglycaemia has a powerful association with adverse prognosis for patients with acute coronary syndromes (ACS). Previous work shows high glucose prevents ischaemic preconditioning and causes electrical and mechanical disruption via PKCα/β activation. The aims of this study were to: 1) determine whether the adverse clinical association of hyperglycaemia in ACS can be replicated in preclinical cellular models of ACS. 2) Ascertain the importance of PKCα/β activation to the deleterious effect of glucose. Methods Freshly isolated rat, guinea pig or rabbit cardiomyocytes were exposed to simulated ischaemia after incubation in the presence of normal (5 mm) or high (20 mm) glucose in the absence or presence of small molecule or tat‐peptide‐linked PKCαβ inhibitors. In each of the 4 conditions, the following hallmarks of cardioprotection were recorded using electrophysiology or fluorescent imaging: cardiomyocyte contraction & survival, action potential stability & time to failure, intracellular calcium & ATP, mitochondrial depolarisation, ischaemia‐sensitive leak current and time to Kir6.2 opening. Results High glucose alone resulted in decreased cardiomyocyte contraction and survival, however, imparted cardioprotection in the presence of PKCα/β inhibitors. This cardioprotective phenotype displayed improvements in all measured parameters and decreased myocardium damage during whole heart coronary ligation experiments. Conclusions High glucose is deleterious to cellular and whole‐heart models of simulated ischaemia, in keeping with the clinical association of hyperglycaemia with adverse outcome in ACS. PKCαβ inhibition revealed high glucose to show a cardioprotective phenotype in this setting. This study suggests the potential for therapeutic application of PKCαβ inhibition in ACS associated with hyperglycaemia.

Funding

This work was supported by the van Geest Cardiovascular Research Fund, University of Leicester (SB, RDR) and the British Heart Foundation (PG/16/14/32039) (SB, RDR), and forms part of the work of the Leicester NIHR Biomedical Research Centre.

History

Citation

The Journal of Physiology, 2019

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Molecular & Cell Biology

Version

  • AM (Accepted Manuscript)

Published in

The Journal of Physiology

Publisher

Wiley, Physiological Society

issn

0022-3751

Acceptance date

2019-06-03

Copyright date

2019

Publisher version

https://physoc.onlinelibrary.wiley.com/doi/abs/10.1113/JP278332

Notes

The file associated with this record is under embargo until 12 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above.

Language

en

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