Myeloid deletion and therapeutic activation of AMPK do not alter atherosclerosis in male or female mice.
adenosine 5′-monophosphate-activated protein kinase
cholesterol
immunometabolism
inflammation
macrophage
Journal
Journal of lipid research
ISSN: 1539-7262
Titre abrégé: J Lipid Res
Pays: United States
ID NLM: 0376606
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
pubmed:
27
9
2020
medline:
26
10
2021
entrez:
26
9
2020
Statut:
ppublish
Résumé
The dysregulation of myeloid-derived cell metabolism can drive atherosclerosis. AMP-activated protein kinase (AMPK) controls various aspects of macrophage dynamics and lipid homeostasis, which are important during atherogenesis. Using LysM-Cre to drive the deletion of both the α1 and α2 catalytic subunits (MacKO), we aimed to clarify the role of myeloid-specific AMPK signaling in male and female mice made acutely atherosclerotic by injection of AAV vector encoding a gain-of-function mutant PCSK9 (PCSK9-AAV) and WD feeding. After 6 weeks of WD feeding, mice received a daily injection of either the AMPK activator A-769662 or a vehicle control for an additional 6 weeks. Following this (12 weeks total), we assessed myeloid cell populations and differences between genotype or sex were not observed. Similarly, aortic sinus plaque size, lipid staining, and necrotic area did not differ in male and female MacKO mice compared with their littermate floxed controls. Moreover, therapeutic intervention with A-769662 showed no treatment effect. There were also no observable differences in the amount of circulating total cholesterol or triglyceride, and only minor differences in the levels of inflammatory cytokines between groups. Finally, CD68+ area and markers of autophagy showed no effect of either lacking AMPK signaling or AMPK activation. Our data suggest that while defined roles for each catalytic AMPK subunit have been identified, complete deletion of myeloid AMPK signaling does not significantly impact atherosclerosis. Additionally, these findings suggest that intervention with the first-generation AMPK activator A-769662 is not able to stem the progression of atherosclerosis.
Identifiants
pubmed: 32978273
pii: S0022-2275(20)60029-3
doi: 10.1194/jlr.RA120001040
pmc: PMC7707174
pii:
doi:
Substances chimiques
AMP-Activated Protein Kinases
EC 2.7.11.31
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1697-1706Subventions
Organisme : CIHR
ID : PJT148634
Pays : Canada
Organisme : CIHR
ID : PJT156136
Pays : Canada
Organisme : CIHR
ID : MSH141981
Pays : Canada
Informations de copyright
Copyright © 2020 LeBlond et al. Published by The American Society for Biochemistry and Molecular Biology, Inc.
Déclaration de conflit d'intérêts
Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article.
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