Statin activation of skeletal ryanodine receptors (RyR1) is a class effect but separable from HMG-CoA reductase inhibition.
Ca2+-release
RyR1
myopathy
ryanodine receptor
single-channel
statin
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
11 2022
11 2022
Historique:
revised:
20
04
2022
received:
13
07
2021
accepted:
28
04
2022
pubmed:
16
6
2022
medline:
6
10
2022
entrez:
15
6
2022
Statut:
ppublish
Résumé
Statins, inhibitors of HMG-CoA reductase, are mainstay treatment for hypercholesterolaemia. However, muscle pain and weakness prevent many patients from benefiting from their cardioprotective effects. We previously demonstrated that simvastatin activates skeletal ryanodine receptors (RyR1), an effect that could be important in initiating myopathy. Using a range of structurally diverse statin analogues, we examined structural features associated with RyR1 activation, aiming to identify statins lacking this property. Compounds were screened for RyR1 activity utilising [ All UK-prescribed statins activated RyR1 at nanomolar concentrations. Cerivastatin, withdrawn from the market due to life-threatening muscle-related side effects, was more effective than currently-prescribed statins and possessed the unique ability to open RyR1 channels independently of cytosolic Ca That cerivastatin activates RyR1 most strongly supports the hypothesis that RyR1 activation is implicated in statin-induced myopathy. Demonstrating that statin regulation of RyR1 and HMG-CoA reductase are separable effects will allow the role of RyR1 in statin-induced myopathy to be further elucidated by the tool compounds we have identified, allowing development of effective cardioprotective statins with improved patient tolerance.
Sections du résumé
BACKGROUND AND PURPOSE
Statins, inhibitors of HMG-CoA reductase, are mainstay treatment for hypercholesterolaemia. However, muscle pain and weakness prevent many patients from benefiting from their cardioprotective effects. We previously demonstrated that simvastatin activates skeletal ryanodine receptors (RyR1), an effect that could be important in initiating myopathy. Using a range of structurally diverse statin analogues, we examined structural features associated with RyR1 activation, aiming to identify statins lacking this property.
EXPERIMENTAL APPROACH
Compounds were screened for RyR1 activity utilising [
KEY RESULTS
All UK-prescribed statins activated RyR1 at nanomolar concentrations. Cerivastatin, withdrawn from the market due to life-threatening muscle-related side effects, was more effective than currently-prescribed statins and possessed the unique ability to open RyR1 channels independently of cytosolic Ca
CONCLUSION AND IMPLICATIONS
That cerivastatin activates RyR1 most strongly supports the hypothesis that RyR1 activation is implicated in statin-induced myopathy. Demonstrating that statin regulation of RyR1 and HMG-CoA reductase are separable effects will allow the role of RyR1 in statin-induced myopathy to be further elucidated by the tool compounds we have identified, allowing development of effective cardioprotective statins with improved patient tolerance.
Identifiants
pubmed: 35703154
doi: 10.1111/bph.15893
pmc: PMC9804224
doi:
Substances chimiques
Acyl Coenzyme A
0
Hydroxymethylglutaryl-CoA Reductase Inhibitors
0
Ryanodine Receptor Calcium Release Channel
0
3-hydroxy-3-methylglutaryl-coenzyme A
1553-55-5
Ryanodine
15662-33-6
Simvastatin
AGG2FN16EV
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4941-4957Subventions
Organisme : British Heart Foundation
ID : PG/19/38/34403
Pays : United Kingdom
Informations de copyright
© 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
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