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Lack of Mitogen-activated Kinase Phosphatase-5 in Macrophages Protects Ldlr-null Mice against Atherogenesis

Zhang, Xinbo
; 
Zhao, Zhiqiang
; 
Baldini, Margaret
; ; 
Tao, Bo
; 
Zhang, Lei
; 
Bennett, Anton M.
; 
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Journal article
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2022-12-29
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Cardiovascular Sciences
Biomedical Education and Data Science
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http://hdl.handle.net/20.500.12613/10125
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ZhaoEtAl-JournalArticle-2022-12.pdf
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http://dx.doi.org/10.1016/j.jvssci.2022.05.048
Abstract
Background: Mitogen-activated protein kinases, including JNK, ERK, and p38 mitogen-activated protein kinase, are critical in regulating the expression of various proinflammatory and anti-inflammatory cytokines and chemokines. Previous work has suggested that the absence of MAP kinase phosphatase-5 (MKP-5) inhibits oxidized low-density lipoprotein (oxLDL)-induced macrophage foam cell formation without influencing the MAKP activation. The current study is to determine the role of macrophage MKP-5 in the pathogenesis of atherosclerosis and underlying mechanisms. Methods: Nine-week-old male congenic MKP-5 deficient (MKP-5–/–) and C57Bl/6J control (WT) mice on an low-density lipoprotein (LDL) receptor knock-out (LDLR–/–) background were fed with a high-fat diet containing 1.25% cholesterol for 14 weeks. Global deficiency of MKP-5 attenuated atherosclerotic plaque formation without altering the lipid profile in vivo. To further elucidate the macrophage-specific effect of MKP-5 in atherogenesis, lethally irradiated LDLR–/– mice were transplanted with wild-type or MKP-5–/– bone marrow and subjected to high-fat feeding. Results: Mice transplanted with MKP-5–/– bone marrow developed smaller atherosclerotic lesions accompanied by decreased lipid deposition and macrophage content compared with wild type. Lack of MKP-5 in macrophages reduced plasma levels of interleukin-1α (IL-1α) and IL-7, elevated anti-inflammatory cytokines IL-1 receptor antagonist (IL-1rn), and IL-4. Mechanistically, lack of MKP-5 in macrophages inhibited ox-LDL-induced foam cell formation through enhanced cholesterol efflux mediated by increased expression of ATP-binding cassette transporters ABCA1 and ABCG1. Conclusions: These data suggest that the myeloid MKP-5 deficiency reduces atherosclerosis progression and foam cell formation by ameliorating cholesterol efflux and inhibiting inflammation.
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Xinbo Zhang, Zhiqiang Zhao, Margaret Baldini, Cheng Zhang, Bo Tao, Lei Zhang, Anton M. Bennett, Jun Yu, Lack of Mitogen-activated Kinase Phosphatase-5 in Macrophages Protects Ldlr-null Mice against Atherogenesis, JVS-Vascular Science, Volume 3, 2022, Page 423, ISSN 2666-3503, https://doi.org/10.1016/j.jvssci.2022.05.048.
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Elsevier
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JVS - Vascular Science, Vol. 3
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