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NAMPT knockdown attenuates atherosclerosis and promotes reverse cholesterol transport in ApoE KO mice with high-fat-induced insulin resistance.

ABSTRACT: NAMPT has been suggested association with atherosclerosis and insulin resistance. However, the impact of NAMPT on atherosclerosis remained unknown. Therefore, the objective of this study was to use a NAMPT loss-of-function approach to investigate the effect of NAMPT on atherosclerosis in hypercholesterolemic mice. We demonstrated that a specific NAMPT knockdown increased plasma HDL-C levels, reduced the plaque area of the total aorta en face and the cross-sectional aortic sinus, decreased macrophage number and apoptosis, and promoted RCT in HFD-fed ApoE KO mice. These changes were accompanied by increased PPAR?, LXR?, ABCA1 and ABCG1 expressions in the liver. NAMPT knockdown also facilitated cholesterol efflux in RAW264.7 cells. We further investigated the effect of NAMPT knockdown on the PPAR?-LXR? pathway of cholesterol metabolism with MK886 (a selective inhibitor of PPAR?) in RAW264.7 macrophages. MK886 abolished the ability of NAMPT knockdown to decrease intracellular cholesterol levels to enhance the rate of (3)H-cholesterol efflux and to increase ABCA1/G1 and LXR? expressions in RAW264.7 macrophages. Our observations demonstrate that NAMPT knockdown exerted antiatherogenic effects by promoting cholesterol efflux and macrophage RCT through the PPAR?- LXR?- ABCA1/G1pathway in vitro and in vivo.

SUBMITTER: Li S

PROVIDER: S-EPMC4882618 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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NAMPT knockdown attenuates atherosclerosis and promotes reverse cholesterol transport in ApoE KO mice with high-fat-induced insulin resistance.

Li Shengbing S Wang Cong C Li Ke K Li Ling L Tian Mingyuan M Xie Jing J Yang Mengliu M Jia Yanjun Y He Junying J Gao Lin L Boden Guenther G Liu Hua H Yang Gangyi G

Scientific reports 20160527

NAMPT has been suggested association with atherosclerosis and insulin resistance. However, the impact of NAMPT on atherosclerosis remained unknown. Therefore, the objective of this study was to use a NAMPT loss-of-function approach to investigate the effect of NAMPT on atherosclerosis in hypercholesterolemic mice. We demonstrated that a specific NAMPT knockdown increased plasma HDL-C levels, reduced the plaque area of the total aorta en face and the cross-sectional aortic sinus, decreased macrop ...[more]

PMID: 27229177

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Project description:ObjectivePreclinical and clinical studies have shown beneficial effects of infusions of apolipoprotein A-I (ApoA-I) on atherosclerosis. ApoA-I is also a target for myeloperoxidase-mediated oxidation, leading in vitro to a loss of its ability to promote ATP-binding cassette transporter A1-dependent macrophage cholesterol efflux. Therefore, we hypothesized that myeloperoxidase-mediated ApoA-I oxidation would impair its promotion of reverse cholesterol transport in vivo and the beneficial effects on atherosclerotic plaques.Approach and resultsApoA-I(-/-) or apolipoprotein E-deficient mice were subcutaneously injected with native human ApoA-I, oxidized human ApoA-I (myeloperoxidase/hydrogen peroxide/chloride treated), or carrier. Although early postinjection (8 hours) levels of total ApoA-I in plasma were similar for native versus oxidized human ApoA-I, native ApoA-I primarily resided within the high-density lipoprotein fraction, whereas the majority of oxidized human ApoA-I was highly cross-linked and not high-density lipoprotein particle associated, consistent with impaired ATP-binding cassette transporter A1 interaction. In ApoA-I(-/-) mice, ApoA-I oxidation significantly impaired reverse cholesterol transport in vivo. In advanced aortic root atherosclerotic plaques of apolipoprotein E-deficient mice, native ApoA-I injections led to significant decreases in lipid content, macrophage number, and an increase in collagen content; in contrast, oxidized human ApoA-I failed to mediate these changes. The decrease in plaque macrophages with native ApoA-I was accompanied by significant induction of their chemokine receptor CCR7. Furthermore, only native ApoA-I injections led to a significant reduction of inflammatory M1 and increase in anti-inflammatory M2 macrophage markers in the plaques.ConclusionsMyeloperoxidase-mediated oxidation renders ApoA-I dysfunctional and unable to (1) promote reverse cholesterol transport, (2) mediate beneficial changes in the composition of atherosclerotic plaques, and (3) pacify the inflammatory status of plaque macrophages.

Dataset Information

NAMPT knockdown attenuates atherosclerosis and promotes reverse cholesterol transport in ApoE KO mice with high-fat-induced insulin resistance.

Publications

NAMPT knockdown attenuates atherosclerosis and promotes reverse cholesterol transport in ApoE KO mice with high-fat-induced insulin resistance.

Similar Datasets

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