High dose rosuvastatin increases ABCA1 transporter in human atherosclerotic plaques in a cholesterol-independent fashion.
ATP Binding Cassette Transporter 1
/ biosynthesis
Aged
Aged, 80 and over
Anticholesteremic Agents
/ administration & dosage
Cholesterol
/ blood
Dose-Response Relationship, Drug
Female
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors
/ administration & dosage
Male
Plaque, Atherosclerotic
/ blood
Rosuvastatin Calcium
/ administration & dosage
ABCA1
Atherosclerosis
Cholesterol efflux
Statins
miR-33b
microRNA
Journal
International journal of cardiology
ISSN: 1874-1754
Titre abrégé: Int J Cardiol
Pays: Netherlands
ID NLM: 8200291
Informations de publication
Date de publication:
15 01 2020
15 01 2020
Historique:
received:
19
01
2019
revised:
10
07
2019
accepted:
30
07
2019
pubmed:
15
8
2019
medline:
24
11
2020
entrez:
15
8
2019
Statut:
ppublish
Résumé
ATP-binding cassette A1 (ABCA1) and G1 (ABCG1) mediate cholesterol efflux from lipid-laden macrophages, thus promoting anti-atherosclerotic outcomes. The mechanism(s) linking treatment with statins and ABCA1/ABCG1 in human atherosclerosis are not fully understood and require further investigation. Therefore, we studied whether short-term treatment with low- or high-dose rosuvastatin may affect ABCA1 and ABCG1 expression in human atherosclerotic plaques. Seventy patients with severe stenosis of the internal carotid artery were randomized to receive low (10 mg/day) or high (40 mg/day) dose rosuvastatin for 12 weeks before elective endarterectomy. As controls, we analyzed a reference group of 10 plaques from subjects with hypercholesterolemia but not receiving statin treatment and an additional set of 11 plaques collected from normocholesterolemic patients. On atherosclerotic plaques, ABCA1 and ABCG1 expression was evaluated at RNA level by qPCR and at protein level by immunoblotting and immunohistochemistry. Both rosuvastatin doses were associated with lower plaque ABCA1 mRNA levels and with a trend toward reduction for ABCG1. However, ABCA1 protein was paradoxically higher in patients treated with high-dose rosuvastatin and was associated with lower levels of miR-33b-5p, a microRNA known as a regulator of ABCA1. Multivariate analyses showed that the effect is cholesterol-independent. Finally, no effects were found for ABCG1 protein. High-dose rosuvastatin increases macrophage ABCA1 protein levels in human atherosclerotic plaque despite mRNA reduction in a mechanism unrelated to plasma cholesterol reduction and potentially involving miR-33b-5p. This pathway may reflect an additional feature contributing to the anti-atherosclerotic effect for high-dose rosuvastatin. ISRCTN16590640.
Sections du résumé
BACKGROUND
ATP-binding cassette A1 (ABCA1) and G1 (ABCG1) mediate cholesterol efflux from lipid-laden macrophages, thus promoting anti-atherosclerotic outcomes. The mechanism(s) linking treatment with statins and ABCA1/ABCG1 in human atherosclerosis are not fully understood and require further investigation. Therefore, we studied whether short-term treatment with low- or high-dose rosuvastatin may affect ABCA1 and ABCG1 expression in human atherosclerotic plaques.
METHODS
Seventy patients with severe stenosis of the internal carotid artery were randomized to receive low (10 mg/day) or high (40 mg/day) dose rosuvastatin for 12 weeks before elective endarterectomy. As controls, we analyzed a reference group of 10 plaques from subjects with hypercholesterolemia but not receiving statin treatment and an additional set of 11 plaques collected from normocholesterolemic patients. On atherosclerotic plaques, ABCA1 and ABCG1 expression was evaluated at RNA level by qPCR and at protein level by immunoblotting and immunohistochemistry.
RESULTS
Both rosuvastatin doses were associated with lower plaque ABCA1 mRNA levels and with a trend toward reduction for ABCG1. However, ABCA1 protein was paradoxically higher in patients treated with high-dose rosuvastatin and was associated with lower levels of miR-33b-5p, a microRNA known as a regulator of ABCA1. Multivariate analyses showed that the effect is cholesterol-independent. Finally, no effects were found for ABCG1 protein.
CONCLUSIONS
High-dose rosuvastatin increases macrophage ABCA1 protein levels in human atherosclerotic plaque despite mRNA reduction in a mechanism unrelated to plasma cholesterol reduction and potentially involving miR-33b-5p. This pathway may reflect an additional feature contributing to the anti-atherosclerotic effect for high-dose rosuvastatin.
TRIAL REGISTRATION
ISRCTN16590640.
Identifiants
pubmed: 31409515
pii: S0167-5273(19)30116-0
doi: 10.1016/j.ijcard.2019.07.094
pii:
doi:
Substances chimiques
ABCA1 protein, human
0
ATP Binding Cassette Transporter 1
0
Anticholesteremic Agents
0
Hydroxymethylglutaryl-CoA Reductase Inhibitors
0
Rosuvastatin Calcium
83MVU38M7Q
Cholesterol
97C5T2UQ7J
Types de publication
Journal Article
Randomized Controlled Trial
Langues
eng
Sous-ensembles de citation
IM
Pagination
249-253Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 Elsevier B.V. All rights reserved.