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Theranostics 2023; 13(10):3419-3433. doi:10.7150/thno.85361 This issue Cite

Research Paper

Lactoferrin attenuates cardiac fibrosis and cardiac remodeling after myocardial infarction via inhibiting mTORC1/S6K signaling pathway

Tianbao Ye1,2#, Zhiwen Yan3#, Cheng Chen4#, Di Wang1, Aiting Wang2, Taixi Li1, Boshen Yang1, Xianting Ding2✉, Chengxing Shen1✉

1. Department of Cardiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
2. Institute for Personalized Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China.
3. Youth Science and Technology Innovation Studio of Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
4. School of Medicine, Tongji University, Shanghai 200092, China.
#These authors contributed equally to this work.

✉ Corresponding authors: Chengxing Shen: Email: shencxedu.cn (C.S.), Tel/Fax: 086-021-64369181; Xianting Ding: Email: dingxiantingedu.cn (X.D.), Tel/Fax: 86-21-62932274.

Citation:
Ye T, Yan Z, Chen C, Wang D, Wang A, Li T, Yang B, Ding X, Shen C. Lactoferrin attenuates cardiac fibrosis and cardiac remodeling after myocardial infarction via inhibiting mTORC1/S6K signaling pathway. Theranostics 2023; 13(10):3419-3433. doi:10.7150/thno.85361. https://www.thno.org/v13p3419.htm
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Abstract

Graphic abstract

Rationale: Myocardial infarction (MI) causes a severe injury response that eventually leads to adverse cardiac remodeling and heart failure. Lactoferrin (Ltf), as a secreted protein, bears multi-pharmacological properties. Present study aims to establish the cardioprotective function and corresponding mechanism of Ltf in MI process.

Methods and results: We performed proteomic analysis in Tregs derived from MI heart, and identified Ltf as a remarkably upregulated secreted protein. However, Ltf was decreased in circulation and positively correlated with cardiac function both in mice and patients after MI. Ltf administration remarkably alleviated cardiac fibrosis and remodeling, improved cardiac function, and reduced incidence of heart failure in mice post-MI. In vitro, Ltf suppressed fibroblast to myofibroblast conversion induced by transforming growth factor-β (TGF-β). Mechanistically, phosphoproteomic landscape analysis revealed that Ltf repressed the activation of mTORC1/S6K/eIF-4B signaling pathway via interaction with CD74 receptor. Administration of mTORC1/S6K/eIF-4B axis agonist MHY1485 abolished the cardioprotective effects of Ltf. Besides, MHY1485 also markedly reversed the effects of Ltf on suppressing the transformation of fibroblast to myofibroblast mediated by TGF-β.

Conclusion: Our study established the cardiac protective role of Ltf in attenuating cardiac remodeling and improving cardiac function by inhibiting the activation of myofibroblasts through suppressing mTORC1/S6K/eIF-4B signaling pathway post-MI. Treatment with Ltf may serve as a potential novel therapeutic intervention in patients with MI.

Keywords: 'cardiac fibrosis', 'myocardial infarction', 'myofibroblast', 'lactoferrin', 'cardiac remodeling'

Citation styles

APA
Ye, T., Yan, Z., Chen, C., Wang, D., Wang, A., Li, T., Yang, B., Ding, X., Shen, C. (2023). Lactoferrin attenuates cardiac fibrosis and cardiac remodeling after myocardial infarction via inhibiting mTORC1/S6K signaling pathway. Theranostics, 13(10), 3419-3433. https://doi.org/10.7150/thno.85361.

ACS
Ye, T.; Yan, Z.; Chen, C.; Wang, D.; Wang, A.; Li, T.; Yang, B.; Ding, X.; Shen, C. Lactoferrin attenuates cardiac fibrosis and cardiac remodeling after myocardial infarction via inhibiting mTORC1/S6K signaling pathway. Theranostics 2023, 13 (10), 3419-3433. DOI: 10.7150/thno.85361.

NLM
Ye T, Yan Z, Chen C, Wang D, Wang A, Li T, Yang B, Ding X, Shen C. Lactoferrin attenuates cardiac fibrosis and cardiac remodeling after myocardial infarction via inhibiting mTORC1/S6K signaling pathway. Theranostics 2023; 13(10):3419-3433. doi:10.7150/thno.85361. https://www.thno.org/v13p3419.htm

CSE
Ye T, Yan Z, Chen C, Wang D, Wang A, Li T, Yang B, Ding X, Shen C. 2023. Lactoferrin attenuates cardiac fibrosis and cardiac remodeling after myocardial infarction via inhibiting mTORC1/S6K signaling pathway. Theranostics. 13(10):3419-3433.

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