Dataset Information

Activation of Nrf2 inhibits atherosclerosis in ApoE^-/- mice through suppressing endothelial cell inflammation and lipid peroxidation.

ABSTRACT:

Background

Nuclear erythroid 2-related factor 2 (Nrf2), a transcription factor, is critically involved in the regulation of oxidative stress and inflammation. However, the role of endothelial Nrf2 in atherogenesis has yet to be defined. In addition, how endothelial Nrf2 is activated and whether Nrf2 can be targeted for the prevention and treatment of atherosclerosis is not explored.

Methods

RNA-sequencing and single-cell RNA sequencing analysis of mouse atherosclerotic aortas were used to identify the differentially expressed genes. In vivo endothelial cell (EC)-specific activation of Nrf2 was achieved by injecting adeno-associated viruses into ApoE^-/- mice, while EC-specific knockdown of Nrf2 was generated in Cdh5^CreCas9^floxed-stopApoE^-/- mice.

Results

Endothelial inflammation appeared as early as on day 3 after feeding of a high cholesterol diet (HCD) in ApoE^-/- mice, as reflected by mRNA levels, immunostaining and global mRNA profiling, while the immunosignal of the end-product of lipid peroxidation (LPO), 4-hydroxynonenal (4-HNE), started to increase on day 10. TNF-α, 4-HNE, and erastin (LPO inducer), activated Nrf2 signaling in human ECs by increasing the mRNA and protein expression of Nrf2 target genes. Knockdown of endothelial Nrf2 resulted in augmented endothelial inflammation and LPO, and accelerated atherosclerosis in Cdh5^CreCas9^floxed-stopApoE^-/- mice. By contrast, both EC-specific and pharmacological activation of Nrf2 inhibited endothelial inflammation, LPO, and atherogenesis.

Conclusions

Upon HCD feeding in ApoE^-/- mice, endothelial inflammation is an earliest event, followed by the appearance of LPO. EC-specific activation of Nrf2 inhibits atherosclerosis while EC-specific knockdown of Nrf2 results in the opposite effect. Pharmacological activators of endothelial Nrf2 may represent a novel therapeutic strategy for the treatment of atherosclerosis.

SUBMITTER: He L

PROVIDER: S-EPMC11247299 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Publications

Activation of Nrf2 inhibits atherosclerosis in ApoE<sup>-/-</sup> mice through suppressing endothelial cell inflammation and lipid peroxidation.

He Lei L Chen Qinghua Q Wang Li L Pu Yujie Y Huang Juan J Cheng Chak Kwong CK Luo Jiang-Yun JY Kang Lijing L Lin Xiao X Xiang Li L Fang Liang L He Ben B Xia Yin Y Lui Kathy O KO Pan Yong Y Liu Jie J Zhang Cheng-Lin CL Huang Yu Y

Redox biology 20240606

<h4>Background</h4>Nuclear erythroid 2-related factor 2 (Nrf2), a transcription factor, is critically involved in the regulation of oxidative stress and inflammation. However, the role of endothelial Nrf2 in atherogenesis has yet to be defined. In addition, how endothelial Nrf2 is activated and whether Nrf2 can be targeted for the prevention and treatment of atherosclerosis is not explored.<h4>Methods</h4>RNA-sequencing and single-cell RNA sequencing analysis of mouse atherosclerotic aortas were ...[more]

PMID: 38870781

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Project description:Background and Purpose: Atherosclerosis is vascular disease of chronic inflammation and lipid disorder, which is a major cause of coronary heart disease. Foam cell formation is key progress during the atherosclerosis development. Insulin-like growth factor (IGF)-1 is a growth hormone that plays a crucial role in growth, metabolism, and homeostasis. Previous studies have demonstrated that increase in circulating IGF-1 can reduce atherosclerotic burden. However, active IGF-1 is characterized with poor tissue retention and is at a very low level in circulation system. Therefore, supplementation of exogenous IGF-1 to restore the physiological level is a promising approach to inhibit atherosclerosis. In this study, we develop a self-assembling, anti-inflammatory drug-modified peptide derived from IGF-1 to mimic IGF-1 bioactivity and simultaneously with an anti-inflammatory property for the treatment of atherosclerosis. Methods: ApoE-/- mice were subcutaneously (s.c.) injected with the different hydrogels or natural IGF-1 protein solution per week and simultaneously fed a high-fat diet for 16 weeks. Atherosclerotic lesion formation and stability were assessed after treatment. Moreover, peritoneal macrophage and serum samples were collected to determine lipid profile and inflammatory cytokines. Concurrently, we determined the effect of bifunctional supramolecular nanofibers/hydrogel on cholesterol efflux, foam cell formation, phenotypic transformation of VSMC to macrophage-like cells, and macrophage polarization in vitro or in vivo. Results: Bifunctional supramolecular nanofibers/hydrogel for the treatment of atherosclerosis was formed by a short peptide consisting of a tetrapeptide SSSR from C-region of growth factor IGF-1, an anti-inflammatory drug naproxen (Npx), and a powerful self-assembling D-peptide DFDF. The resulting hydrogel of Npx-DFDFGSSSR (Hydrogel 1, H1) possessed both the anti-inflammatory and IGF-1 mimicking properties, and it efficiently promoted the expression of ABCA1 and ABCG1, thereby significantly reducing cholesterol accumulation in macrophages and preventing foam cell formation. Moreover, H1 markedly inhibited the transformation of vascular smooth muscle cells (VSMCs) into macrophage-like cells which also contributed to foam cell formation. In addition, H1 significantly reduced the inflammatory response in vitro and in vivo. Most importantly, the IGF-1 mimetic peptide showed comparable performance to IGF-1 in vivo and inhibited atherosclerosis by markedly reducing lesion area and enhancing plaque stability. Conclusions: Our study provides a novel supramolecular nanomaterial to inhibit pathological progress of atherosclerosis through regulating cholesterol efflux and inflammation, which may contribute to the development of a promising nanomedicine for the treatment of atherosclerosis in the clinic.

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Dataset Information

Activation of Nrf2 inhibits atherosclerosis in ApoE^-/- mice through suppressing endothelial cell inflammation and lipid peroxidation.

Background

Methods

Results

Conclusions

Publications

Activation of Nrf2 inhibits atherosclerosis in ApoE<sup>-/-</sup> mice through suppressing endothelial cell inflammation and lipid peroxidation.

Similar Datasets

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Dataset Information

Activation of Nrf2 inhibits atherosclerosis in ApoE-/- mice through suppressing endothelial cell inflammation and lipid peroxidation.

Background

Methods

Results

Conclusions

Publications

Activation of Nrf2 inhibits atherosclerosis in ApoE<sup>-/-</sup> mice through suppressing endothelial cell inflammation and lipid peroxidation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Activation of Nrf2 inhibits atherosclerosis in ApoE^-/- mice through suppressing endothelial cell inflammation and lipid peroxidation.