AMPK-mediated regulation of endogenous cholesterol synthesis does not affect atherosclerosis in a murine Pcsk9-AAV model

doi:10.1016/j.atherosclerosis.2024.117608

. 2024 Jun 3:117608.

doi: 10.1016/j.atherosclerosis.2024.117608. Online ahead of print.

AMPK-mediated regulation of endogenous cholesterol synthesis does not affect atherosclerosis in a murine Pcsk9-AAV model

Tyler K T Smith¹, Peyman Ghorbani¹, Nicholas D LeBlond², Julia R C Nunes¹, Conor O'Dwyer¹, Nia Ambursley², Claire Fong-McMaster³, Lucía Minarrieta¹, Leah A Burkovsky², Rama El-Hakim², Natasha A Trzaskalski⁴, Cassandra A A Locatelli⁴, Cameron Stotts⁴, Ciara Pember², Katey J Rayner⁵, Bruce E Kemp⁶, Kim Loh⁷, Mary-Ellen Harper¹, Erin E Mulvihill⁸, Julie St-Pierre¹, Morgan D Fullerton⁹

Affiliations

¹ Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; Centre for Infection, Immunity and Inflammation, Ottawa, ON, Canada; Ottawa Institute of Systems Biology, Ottawa, ON, Canada.
² Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
³ Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; Ottawa Institute of Systems Biology, Ottawa, ON, Canada.
⁴ Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; University of Ottawa Heart Institute, Ottawa, ON, Canada.
⁵ Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; Centre for Infection, Immunity and Inflammation, Ottawa, ON, Canada; University of Ottawa Heart Institute, Ottawa, ON, Canada.
⁶ Protein Chemistry and Metabolism, St. Vincent's Institute of Medical Research, Fitzroy, Australia; Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia.
⁷ Diabetes and Metabolic Disease, St. Vincent's Institute of Medical Research, Fitzroy, Australia; Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia.
⁸ Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; Centre for Infection, Immunity and Inflammation, Ottawa, ON, Canada; Ottawa Institute of Systems Biology, Ottawa, ON, Canada; University of Ottawa Heart Institute, Ottawa, ON, Canada.
⁹ Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; Centre for Infection, Immunity and Inflammation, Ottawa, ON, Canada; Centre for Catalysis Research and Innovation, Ottawa, ON, Canada; Ottawa Institute of Systems Biology, Ottawa, ON, Canada. Electronic address: morgan.fullerton@uottawa.ca.

PMID: 38880706
DOI: 10.1016/j.atherosclerosis.2024.117608

AMPK-mediated regulation of endogenous cholesterol synthesis does not affect atherosclerosis in a murine Pcsk9-AAV model

Tyler K T Smith et al. Atherosclerosis. 2024.

. 2024 Jun 3:117608.

doi: 10.1016/j.atherosclerosis.2024.117608. Online ahead of print.

Authors

Affiliations

¹ Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; Centre for Infection, Immunity and Inflammation, Ottawa, ON, Canada; Ottawa Institute of Systems Biology, Ottawa, ON, Canada.
² Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
³ Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; Ottawa Institute of Systems Biology, Ottawa, ON, Canada.
⁴ Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; University of Ottawa Heart Institute, Ottawa, ON, Canada.
⁵ Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; Centre for Infection, Immunity and Inflammation, Ottawa, ON, Canada; University of Ottawa Heart Institute, Ottawa, ON, Canada.
⁶ Protein Chemistry and Metabolism, St. Vincent's Institute of Medical Research, Fitzroy, Australia; Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia.
⁷ Diabetes and Metabolic Disease, St. Vincent's Institute of Medical Research, Fitzroy, Australia; Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia.
⁸ Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; Centre for Infection, Immunity and Inflammation, Ottawa, ON, Canada; Ottawa Institute of Systems Biology, Ottawa, ON, Canada; University of Ottawa Heart Institute, Ottawa, ON, Canada.
⁹ Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; Centre for Infection, Immunity and Inflammation, Ottawa, ON, Canada; Centre for Catalysis Research and Innovation, Ottawa, ON, Canada; Ottawa Institute of Systems Biology, Ottawa, ON, Canada. Electronic address: morgan.fullerton@uottawa.ca.

PMID: 38880706
DOI: 10.1016/j.atherosclerosis.2024.117608

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 Pcsk9^D374Y-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: AMPK; Atherosclerosis; Cholesterol; HMGCR; Hematopoiesis; Immunometabolism; Inflammation.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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AMPK-mediated regulation of endogenous cholesterol synthesis does not affect atherosclerosis in a murine Pcsk9-AAV model

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AMPK-mediated regulation of endogenous cholesterol synthesis does not affect atherosclerosis in a murine Pcsk9-AAV model

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