A novel form of glycolytic metabolism-dependent cardioprotection revealed by PKCα and β inhibition.
Animals
Glucose
/ pharmacology
Glycolysis
/ drug effects
Guinea Pigs
Hyperglycemia
/ drug therapy
Male
Myocardial Ischemia
/ drug therapy
Myocardial Reperfusion Injury
/ drug therapy
Myocardium
/ metabolism
Myocytes, Cardiac
/ drug effects
Protective Agents
/ pharmacology
Protein Kinase C beta
/ antagonists & inhibitors
Protein Kinase C-alpha
/ antagonists & inhibitors
Rabbits
Rats
Rats, Wistar
Cardiomyocyte
Cardioprotection
Glucose
Ischaemia
PKC
Journal
The Journal of physiology
ISSN: 1469-7793
Titre abrégé: J Physiol
Pays: England
ID NLM: 0266262
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
17
05
2019
accepted:
24
06
2019
pubmed:
27
6
2019
medline:
21
8
2020
entrez:
27
6
2019
Statut:
ppublish
Résumé
Acute hyperglycaemia at the time of a heart attack worsens the outcome for the patient. Acute hyperglycaemia is not limited to diabetic patients and can be due to a stress response in non-diabetics. This study suggests that the damaging cardiac effects of hyperglycaemia can be reversed by selective PKC inhibition. If PKCα/β isoforms are inhibited, then high glucose itself becomes protective against ischaemic damage. Selective PKC inhibition may therefore be a useful therapeutic tool to limit the damage that can occur during a heart attack by stress-induced hyperglycaemia. Hyperglycaemia has a powerful association with adverse prognosis for patients with acute coronary syndromes (ACS). Previous work shows that high glucose prevents ischaemic preconditioning and causes electrical and mechanical disruption via protein kinase C α/β (PKCα/β) activation. The present study aimed to: (i) determine whether the adverse clinical association of hyperglycaemia in ACS can be replicated in preclinical cellular models of ACS and (ii) determine the importance of PKCα/β activation to the deleterious effect of glucose. 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 four conditions, the following hallmarks of cardioprotection were recorded using electrophysiology or fluorescence imaging: cardiomyocyte contraction and survival, action potential stability and time to failure, intracellular calcium and ATP, mitochondrial depolarization, ischaemia-sensitive leak current, and time to K
Substances chimiques
Protective Agents
0
Protein Kinase C beta
EC 2.7.11.13
Protein Kinase C-alpha
EC 2.7.11.13
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4481-4501Subventions
Organisme : British Heart Foundation
ID : PG/19/18/34280
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : British Heart Foundation
ID : PG/16/14/32039
Pays : United Kingdom
Informations de copyright
© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.
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