BAG3 Alleviates Atherosclerosis by Inhibiting Endothelial-to-Mesenchymal Transition via Autophagy Activation

Hongtao Diao; Kaili Wu; Dingming Lan; Dongwei Wang; Jingjing Zhao; Bingying Huang; Xiaoqi Shao; Ruonan Wang; Huiling Tan; Xinyuan Tang; Meiling Yan; Yue Zhang

doi:10.3390/genes13081338

BAG3 Alleviates Atherosclerosis by Inhibiting Endothelial-to-Mesenchymal Transition via Autophagy Activation

Genes (Basel). 2022 Jul 26;13(8):1338. doi: 10.3390/genes13081338.

Authors

Hongtao Diao^{1

2}, Kaili Wu^{1

2}, Dingming Lan^{1

2}, Dongwei Wang^{1

2}, Jingjing Zhao^{1

2}, Bingying Huang^{1

2}, Xiaoqi Shao^{1

2}, Ruonan Wang^{1

2}, Huiling Tan^{1

2}, Xinyuan Tang^{1

2}, Meiling Yan^{1

2}, Yue Zhang^{1

2}

Affiliations

¹ Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China.
² Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China.

Abstract

Atherosclerosis is a chronic systemic inflammatory disease that causes severe cardiovascular events. B cell lymphoma 2-associated athanogene (BAG3) was proven to participate in the regulation of tumor angiogenesis, neurodegenerative diseases, and cardiac diseases, but its role in atherosclerosis remains unclear. Here, we aim to investigate the role of BAG3 in atherosclerosis and elucidate the potential molecular mechanism. In this study, ApoE^-/- mice were given a tail-vein injection of BAG3-overexpressing lentivirus and fed a 12-week high-fat diet (HFD) to investigate the role of BAG3 in atherosclerosis. The overexpression of BAG3 reduced plaque areas and improved atherosclerosis in ApoE^-/- mice. Our research proves that BAG3 promotes autophagy in vitro, contributing to the suppression of EndMT in human umbilical vein endothelial cells (HUVECs). Mechanically, autophagy activation is mediated by BAG3 via the interaction between BAG3 and its chaperones HSP70 and HSPB8. In conclusion, BAG3 facilitates autophagy activation via the formation of the chaperone-assisted selective autophagy (CASA) complex interacting with HSP70 and HSPB8, leading to the inhibition of EndMT during the progression of atherosclerosis and indicating that BAG3 is a potential therapeutic target for atherosclerosis.

Keywords: BAG3; CASA complex; EndMT; atherosclerosis; autophagy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing* / genetics
Animals
Apoptosis Regulatory Proteins* / genetics
Atherosclerosis* / genetics
Autophagy / genetics
Epithelial-Mesenchymal Transition*
HSP70 Heat-Shock Proteins
Human Umbilical Vein Endothelial Cells / metabolism
Humans
Mice
Mice, Knockout, ApoE
Molecular Chaperones / metabolism

Substances

Adaptor Proteins, Signal Transducing
Apoptosis Regulatory Proteins
BAG3 protein, human
Bag3 protein, mouse
HSP70 Heat-Shock Proteins
Molecular Chaperones

Grants and funding

This work was funded by the Youth Innovation Talents Project of Colleges and Universities in Guangdong Province (grant number 2019KQNCX058) and the Key Project of Guangdong Basic and Applied Basic Research Foundation (grant number 2021A1515111043).