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Chaetocin attenuates atherosclerosis progression and inhibits vascular smooth muscle cell phenotype switching

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Abstract

We aimed to explore the effect of chaetocin on atherosclerosis and its possible mechanism. In vitro, we observed that chaetocin treatment significantly inhibited the proliferation of VSMCs in concentration- and time-dependent manner. We also found that chaetocin suppressed the migration of VSMCs. Moreover, chaetocin treatment induced a contractile phenotype in VSMCs by increasing α-SMA and SM22α expression. In addition, chaetocin treatment attenuated the accumulation of H3K9me3 on VSMCs contractile gene promoters, which promoted the expression of α-SMA and SM22α. In vivo, chaetocin treatment decreased the H3K9me3 expression, diminished atherosclerotic plaque formation, and increased plaque stability by decreasing necrotic core area and lipid accumulation and increasing collagen content and contractile VSMC phenotype. We demonstrated a new function of chaetocin in inhibiting atherosclerosis progression and increasing plaque stability partly by inhibiting pathological phenotypic switching of VSMCs. These newly identified roles of chaetocin might provide a novel therapeutic target in atherosclerosis.

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Abbreviations

VSMCs:

Vascular smooth muscle cells

ApoE:

Apolipoprotein E

ECM:

Extracellular matrix

α-SMA:

α-Smooth muscle actin

SFM:

Serum-free media

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Acknowledgements

We thank the other investigators, the staff, and the participants of the present study for their valuable contributions.

Funding

This work was supported by grants from the National Key Research and Development Plan (2018YFC1314900 and 2018YFC1314905), the National Natural Science Foundation of China (81170759, 81770813, 82070866, and 82100876), the Science and Technology Commission of Shanghai Municipality (15411960600), and Joint Funds for the Innovation of Science and Technology, Fujian Province (No. 2020Y9106).

Shanghai Municipal Key Clinical Specialty which granted to Dr. Lian-Xi Li.

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Author notes

  1. Ming-Yun Chen, Zhi-Hui Zhang and Jiang-Feng Ke contributed equally to this work.

Authors and Affiliations

  1. Department of Endocrinology and Metabolism, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, 200233, Shanghai, People’s Republic of China

    Ming-Yun Chen, Zhi-Hui Zhang, Jiang-Feng Ke, Ting-Ting Li, Jun-Xi Lu & Lian-Xi Li

  2. Department of Endocrinology, the First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, People’s Republic of China

    Ming-Yun Chen

  3. Department of Emergency, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233, People’s Republic of China

    Mei-Fang Li

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Contributions

Li LX designed the study, supervised the work, and reviewed and edited the manuscript. Chen MY, Zhang ZH, and Ke JF performed the studies. Chen MY wrote the manuscript. Li TT, Li MF, and Lu JX researched the data and reviewed the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Lian-Xi Li.

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Ethics Approval

All institutional and national guidelines for the care and use of laboratory animals were followed and approved by the Institutional Animal Care and Use Committees at Shanghai Jiao Tong University Affiliated Sixth People’s Hospital. This article does not contain any studies with humans.

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The authors declare no competing interests.

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Associate Editor Joost Sluijter oversaw the review of this article.

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Supplementary Information

Below is the link to the electronic supplementary material.

12265_2022_10258_MOESM1_ESM.jpg

Supplementary file1 (JPG 217 kb) The comparison of lipid profile between two groups a Quantification of serum total cholesterol levels. b Quantification of serum triglyceride levels. c Quantification of serum free fatty acid levels. d Quantification of serum low density lipoprotein-cholesterol levels. f Quantification of serum high density lipoprotein-cholesterol levels. n = 9 for each group. Data was expressed as mean ± SEM. Statistical comparisons were made using t-test. *p < 0.05 vs control group.

12265_2022_10258_MOESM2_ESM.jpg

Supplementary file2 (JPG 1410 kb) Chaetocin reduces VSMCs apoptosis in plaque a Representative image of apoptosis was assessed by staining for TUNEL (green) in cross-sections from the aortic root. b Quantification assessment of apoptosis rate. n=6 for control group and n=5 for chaetocin treatment group. Data was expressed as mean ± SEM. Statistical comparisons were made using t-test. **p < 0.01 vs control group.

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Chen, MY., Zhang, ZH., Ke, JF. et al. Chaetocin attenuates atherosclerosis progression and inhibits vascular smooth muscle cell phenotype switching. J. of Cardiovasc. Trans. Res. 15, 1270–1282 (2022). https://doi.org/10.1007/s12265-022-10258-5

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