Blocking ADAM8 in Heart Macrophages Boosts Repair After Heart Attack
Deleting ADAM8 in macrophages activates autophagy, curbs inflammation, and enhances blood vessel regrowth after myocardial infarction in mice.
Summary
Researchers discovered that ADAM8, a protein highly expressed in macrophages after heart attack, impairs cardiac repair by suppressing autophagy and angiogenesis while amplifying inflammation. Using macrophage-specific ADAM8 knockout mice, they showed that deleting this gene improved heart function, reduced fibrosis, and boosted blood vessel regrowth post-MI. Mechanistically, ADAM8 binds to ANXA2 and phosphorylates it at Ser26, which in turn activates mTOR at Ser2448, blocking autophagy. Removing ADAM8 reversed this chain, restoring autophagy and shifting macrophages toward a pro-repair, pro-angiogenic phenotype. The anti-cancer drug bevacizumab reversed survival benefits, confirming VEGFA-driven angiogenesis as a key output. Elevated ADAM8 was also confirmed in plasma of human AMI patients, suggesting translational relevance.
Detailed Summary
Heart attacks trigger a complex inflammatory and repair response in which macrophages play a dual role — clearing debris while also promoting tissue healing and new blood vessel formation. When this balance tips toward excessive inflammation and insufficient angiogenesis, heart function deteriorates and scar tissue expands. Understanding the molecular switches controlling macrophage behavior after MI is therefore critical for developing new therapies.
This study from Southeast University focused on ADAM8 (A Disintegrin and Metalloproteinase 8), a multifunctional enzyme first identified in macrophages. The researchers measured ADAM8 levels in plasma from 90 enrolled patients (70 with AMI, 20 controls) and found significantly elevated ADAM8 in AMI patients. In mice, ADAM8 expression peaked in cardiac macrophages in the days following LAD artery ligation, establishing a strong disease-associated expression pattern.
To establish causality, the team generated macrophage-specific ADAM8 knockout (KO) mice using CRISPR/Cas9 with a Lyz2-Cre driver. KO mice after MI showed markedly improved cardiac function by echocardiography, enhanced angiogenesis in the infarct zone, reduced inflammatory cytokines (IL-1β, IL-18, TNF-α), and less cardiac fibrosis compared to floxed controls. Bone marrow transplantation experiments reproduced the KO phenotype in recipient wild-type mice, confirming the macrophage-intrinsic mechanism. Conversely, AAV6-CD68-Adam8-mediated overexpression of ADAM8 specifically in macrophages reversed these benefits. Critically, treatment with bevacizumab — a clinically approved anti-VEGF biologic — abolished the survival advantage of KO mice, directly implicating VEGFA-driven angiogenesis as a central downstream effector.
RNA sequencing of bone marrow-derived macrophages (BMDMs) from KO mice revealed autophagy as the top upregulated pathway. This was confirmed biochemically: KO BMDMs showed decreased p-mTOR (Ser2448), decreased p62 accumulation, and increased LC3II/I ratios — hallmarks of active autophagy flux. Blocking autophagy pharmacologically reversed the pro-angiogenic and anti-inflammatory phenotype of KO macrophages, establishing autophagy as mechanistically necessary. Using co-immunoprecipitation combined with mass spectrometry and proteomics, ADAM8 was found to physically bind ANXA2 (Annexin A2) and phosphorylate it at Ser26. This phosphorylation event promoted downstream mTOR activation at Ser2448, suppressing autophagy. Mutant ANXA2 constructs mimicking or blocking Ser26 phosphorylation confirmed this pathway directionality.
Collectively, the study defines a linear ADAM8→ANXA2(pSer26)→mTOR(pSer2448)→autophagy suppression axis in cardiac macrophages that drives post-MI inflammation and impairs angiogenesis. By targeting this pathway, either genetically or pharmacologically, the inflammatory-to-repair macrophage transition is accelerated, offering a compelling new therapeutic target for myocardial infarction treatment.
Key Findings
- ADAM8 is significantly elevated in plasma of AMI patients and in cardiac macrophages of MI mice.
- Macrophage-specific ADAM8 knockout improves cardiac function, angiogenesis, and reduces fibrosis post-MI.
- ADAM8 binds ANXA2 and phosphorylates Ser26, activating mTOR and suppressing protective autophagy.
- Autophagy activation in ADAM8-KO macrophages increases VEGFA secretion and reduces IL-1β, IL-18, TNF-α.
- Bevacizumab (anti-VEGF) reverses survival benefits of ADAM8 KO, confirming angiogenesis as key output.
Methodology
Macrophage-specific ADAM8 KO mice were generated via CRISPR/Cas9 (Lyz2-Cre driver), with LAD ligation used to model MI. Mechanistic studies employed RNA sequencing, proteomics, co-immunoprecipitation/mass spectrometry, bone marrow transplantation, and AAV6-mediated macrophage-specific overexpression in vivo, complemented by pharmacological autophagy modulation in vitro.
Study Limitations
The study relied exclusively on male mice, limiting generalizability across sexes. All mechanistic work was performed in rodent BMDMs, and direct validation in human macrophages or cardiac tissue is lacking. The clinical cohort was small (n=90, single center) and observational, precluding causal inference in humans.
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