Amphiregulin improves ventricular remodeling after myocardial infarction by modulating autophagy and apoptosis.

Abstract

Myocardial infarction (MI) is defined as sudden ischemic death of myocardial tissue. Amphiregulin (Areg) regulates cell survival and is crucial for the healing of tissues after damage. However, the functions and mechanisms of Areg after MI remain unclear. Here, we aimed to investigate Areg's impact on myocardial remodeling. Mice model of MI was constructed and Areg-/- mice were used. Expression of Areg was analyzed using western blotting, RT-qPCR, flow cytometry, and immunofluorescence staining. Echocardiographic analysis, Masson's trichrome, and triphenyltetrazolium chloride staining were used to assess cardiac function and structure. RNA sequencing was used for unbiased analysis. Apoptosis and autophagy were determined by western blotting, TUNEL staining, electron microscopy, and mRFP-GFP-LC3 lentivirus. Lysosomal acidity was determined by Lysotracker staining. Areg was elevated in the infarct border zone after MI. It was mostly secreted by macrophages. Areg deficiency aggravated adverse ventricular remodeling, as reflected by worsening cardiac function, a lower survival rate, increased scar size, and interstitial fibrosis. RNA sequencing analyses showed that Areg related to the epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase/protein kinase B (PI3K-Akt), mammalian target of rapamycin (mTOR) signaling pathways, V-ATPase and lysosome pathways. Mechanistically, Areg exerts beneficial effects via increasing lysosomal acidity to promote autophagosome clearance, and activating the EGFR/PI3K/Akt/mTOR signaling pathway, subsequently inhibiting excessive autophagosome formation and apoptosis in cardiomyocytes. This study provides a novel evidence for the role of Areg in inhibiting ventricular remodeling after MI by regulating autophagy and apoptosis and identifies Areg as a potential therapeutic target in ventricular remodeling after MI.

• Authors: Nana Li, Ni Xia, Junyi He, Meilin Liu, Muyang Gu, Yuzhi Lu, Haoyi Yang, Zhiheng Hao, Lingfeng Zha, Xuhong Wang, Weimin Wang, Desheng Hu, Jiong Hu, Xiang Cheng
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 38 Issue 4 Pg. e23488 (Feb 29 2024) ISSN: 1530-6860 [Electronic] United States
• PMID: 38358359 (Publication Type: Journal Article)
• Copyright: © 2024 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.

Chemical References

• Amphiregulin
• ErbB Receptors
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Areg protein, mouse

Topics

• Animals
• Mice
• Amphiregulin (genetics)
• Apoptosis
• Autophagy
• ErbB Receptors
• Mammals
• Myocardial Infarction
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Ventricular Remodeling