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AMPK-mediated regulation of endogenous cholesterol synthesis does not affect atherosclerosis in a murine Pcsk9-AAV model
Smith, Tyler K. T. Ghorbani, Peyman LeBlond, Nicholas D. Nunes, Julia R. C. O'Dwyer, Conor Ambursley, Nia Fong-McMaster, Claire Minarrieta, Lucía Burkovsky, Leah A. El-Hakim, Rama
Smith, Tyler K. T.
Ghorbani, Peyman
LeBlond, Nicholas D.
Nunes, Julia R. C.
O'Dwyer, Conor
Ambursley, Nia
Fong-McMaster, Claire
Minarrieta, Lucía
Burkovsky, Leah A.
El-Hakim, Rama
Author
Smith, Tyler K. T.
Ghorbani, Peyman
LeBlond, Nicholas D.
Nunes, Julia R. C.
O'Dwyer, Conor
Ambursley, Nia
Fong-McMaster, Claire
Minarrieta, Lucía
Burkovsky, Leah A.
El-Hakim, Rama
Trzaskalski, Natasha A.
Locatelli, Cassandra A. A.
Stotts, Cameron
Pember, Ciara
Rayner, Katey J.
Kemp, Bruce E.
Loh, Kim
Harper, Mary-Ellen
Mulvihill, Erin E.
St-Pierre, Julie
Fullerton, Morgan D.
Ghorbani, Peyman
LeBlond, Nicholas D.
Nunes, Julia R. C.
O'Dwyer, Conor
Ambursley, Nia
Fong-McMaster, Claire
Minarrieta, Lucía
Burkovsky, Leah A.
El-Hakim, Rama
Trzaskalski, Natasha A.
Locatelli, Cassandra A. A.
Stotts, Cameron
Pember, Ciara
Rayner, Katey J.
Kemp, Bruce E.
Loh, Kim
Harper, Mary-Ellen
Mulvihill, Erin E.
St-Pierre, Julie
Fullerton, Morgan D.
Abstract
Background and aims
Dysregulated cholesterol metabolism is a hallmark of atherosclerotic cardiovascular diseases, yet our understanding of how endogenous cholesterol synthesis affects atherosclerosis is not clear. The energy sensor AMP-activated protein kinase (AMPK) phosphorylates and inhibits the rate-limiting enzyme in the mevalonate pathway HMG-CoA reductase (HMGCR). Recent work demonstrated that when AMPK-HMGCR signaling was compromised in an Apoe-/- model of hypercholesterolemia, atherosclerosis was exacerbated due to elevated hematopoietic stem and progenitor cell mobilization and myelopoiesis. We sought to validate the significance of the AMPK-HMGCR signaling axis in atherosclerosis using a non-germline hypercholesterolemia model with functional ApoE.
Methods
Male and female HMGCR S871A knock-in (KI) mice and wild-type (WT) littermate controls were made atherosclerotic by intravenous injection of a gain-of-function Pcsk9D374Y-adeno-associated virus followed by high-fat and high-cholesterol atherogenic western diet feeding for 16 weeks.
Results
AMPK activation suppressed endogenous cholesterol synthesis in primary bone marrow-derived macrophages from WT but not HMGCR KI mice, without changing other parameters of cholesterol regulation. Atherosclerotic plaque area was unchanged between WT and HMGCR KI mice, independent of sex. Correspondingly, there were no phenotypic differences observed in hematopoietic progenitors or differentiated immune cells in the bone marrow, blood, or spleen, and no significant changes in systemic markers of inflammation. When lethally irradiated female mice were transplanted with KI bone marrow, there was similar plaque content relative to WT.
Conclusions
Given previous work, our study demonstrates the importance of preclinical atherosclerosis model comparison and brings into question the importance of AMPK-mediated control of cholesterol synthesis in atherosclerosis.
Keywords
atherosclerosis, AMPK, HMGCR, cholesterol, inflammation, hematopoiesis, immunometabolism
Date
2024
Type
Journal article
Journal
Atherosclerosis
Book
Volume
397
Issue
Page Range
Article Number
Article 117608
ACU Department
Faculty of Health Sciences
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Open Access Status
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Controlled
Controlled
Controlled