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Cited by 1Atherosclerosis and Cardiovascular DiseasesCholesterol and Lipid MetabolismLipoproteins and Cardiovascular Health

Enhanced Akt3 kinase activity reduces atherosclerosis in hyperlipidemic mice in a gender-dependent manner

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Zhang, Lifang, Altemus, Jessica, Ding, Liang, Cherepanova, Olga, Byzova, Tatiana V., Podrez, Eugene A.·2023·Journal of Biological Chemistry
DOI 10.1016/j.jbc.2023.105425PMC PMC10716582
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Abstract

Akt3 is one of the three members of the serine/threonine protein kinase B (AKT) family, which regulates multiple cellular processes. We have previously demonstrated that global knockout of Akt3 in mice promotes atherogenesis in a macrophage-dependent manner. Whether enhanced Akt3 kinase activity affects atherogenesis is not known. In this study, we crossed atherosclerosis-prone ApoE −/− mice with a mouse strain that has enhanced Akt3 kinase activity (Akt3 nmf350 ) and assessed atherosclerotic lesion formation and the role of macrophages in atherogenesis. Significant reduction in atherosclerotic lesion area and macrophage accumulation in lesions were observed in ApoE −/− /Akt3 nmf350 mice fed a Western-type diet. Experiments using chimeric ApoE −/− mice with either ApoE −/− /Akt3 nmf350 bone marrow or ApoE −/− bone marrow cells showed that enhanced Akt3 activity specifically in bone marrow-derived cells is atheroprotective. The atheroprotective effect of Akt3 nmf350 was more pronounced in male mice. In line with this result, the release of the pro-inflammatory cytokines IL-6, MCP1, TNF-α, and MIP-1α was reduced by macrophages from male but not female ApoE −/− /Akt3 nmf350 mice. Levels of IL-6 and TNF-α were also reduced in atherosclerotic lesions of ApoE −/− /Akt3 nmf350 male mice compared to ApoE −/− mice. Macrophages from male ApoE −/− /Akt3 nmf350 mice were also more resistant to apoptosis in vitro and in vivo and tended to have more pronounced M2 polarization in vitro . These findings demonstrated that enhanced Akt3 kinase activity in macrophages protects mice from atherosclerosis in hyperlipidemic mice in a gender-dependent manner.

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Cited by

Sorted by citations

Authors
Zhang, L., Altemus, J., Ding, L., Cherepanova, O., Byzova, T. V., & Podrez, E. A.
Affiliations
  • Cleveland State University (US)
  • Cleveland Clinic (US)
Corresponding author
Podrez, Eugene A.
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2023-12
Volume
299
Issue
12
Pages
105425
ISSN
0021-9258 (ISSN-L)
DOI
10.1016/j.jbc.2023.105425
PMC
PMC10716582
OpenAlex
W4388347158
Cited by
1
References
1
Citations by year
2026: 1
FWCI
0.11
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
National Institutes of Health (RO1 142772, RO1 HL 126738, RO1 HL 150193)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Keywords
AKT3, atherosclerosis, hyperlipidemia, macrophages, gender differences, ApoE-deficient mice, bone marrow-derived cells, M2 macrophage polarization, macrophage apoptosis, inflammatory cytokines, Western diet, atheroprotection
MeSH terms
Animals, Apolipoproteins E, Hyperlipidemias, Male, Mice, Inbred C57BL, Tumor Necrosis Factor-alpha, Interleukin-6, Mice, Knockout, Atherosclerosis, Proto-Oncogene Proteins c-akt, Mice

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