ADAM8 deficiency in macrophages promotes cardiac repair after myocardial infarction via ANXA2-mTOR-autophagy pathway

作者：Zhenjun Ji, Jiaqi Guo, Rui Zhang, Wenjie Zuo, Yang Xu, Yangyang Qu, Zaixiao Tao, Xinxin Li, Yongjun Li, Yuyu Yao, Genshan Ma · 发表于：Journal of Advanced Research · 年份：2024 · DOI：10.1016/j.jare.2024.07.037 · 被引用次数：22 · 研究领域：Cardiac Fibrosis and Remodeling、Immune cells in cancer、Atherosclerosis and Cardiovascular Diseases

INTRODUCTION: A disintegrin and metalloproteinase 8 (ADAM8), a crucial regulator in macrophages, is closely associated with cardiovascular disease progression. OBJECTIVES: This study aimed to explore how ADAM8 regulates macrophage function to inhibit cardiac repair after myocardial infarction (MI). METHODS: , Flox) were established using the CRISPR/Cas9 system. Bone marrow transplantation was performed, and macrophage-specific ADAM8-overexpressing adeno-associated virus (AAV6-CD68-Adam8) was produced. Finally, proteomics, RNA sequencing, and co-immunoprecipitation/mass spectrometry (COIP/MS) were used to explore the underlying mechanisms involved. RESULTS: ADAM8 was highly expressed in the plasma of patients with acute myocardial infarction (AMI) and in cardiac macrophages derived from AMI mice. ADAM8 KO mice exhibited enhanced angiogenesis, suppressed inflammation, reduced cardiac fibrosis, and improved cardiac function during AMI, which were reversed by overexpressing macrophage-specific ADAM8 and intervention with the clinical anti-angiogenic biologic bevacizumab. Bone marrow transplantation experiments produced ADAM8 KO phenotypes. RNA sequencing showed that autophagy was activated in bone marrow-derived macrophages (BMDMs) with ADAM8 KO, which was confirmed via p-mTOR Ser2448/mTOR, p62, and LC3II/I detection. Autophagy inactivation suppressed angiogenic factor release and promoted inflammation in BMDMs with ADAM8 KO. Mechanistically, ADAM8 could bind to ANXA2 and promote...