Circulation Research | Acetyltransferase MOF Regulates Macrophage Inflammation and Abdominal Aortic Aneurysm Formation

This study reveals the core role of the epigenetic regulator MOF in the pathogenesis of abdominal aortic aneurysms, providing new experimental design insights for interventions targeting macrophage polarization states.

 

Literature Overview

The article "Acetyltransferase MOF Regulates Macrophage Inflammation in Abdominal Aortic Aneurysms," published in Circulation Research, systematically explores how the histone acetyltransferase MOF regulates the inflammatory phenotype of macrophages through epigenetic modifications, thereby driving the onset and progression of abdominal aortic aneurysms.

Background Knowledge

Abdominal aortic aneurysm (AAA) is a cardiovascular disease with an extremely high mortality rate, characterized by chronic inflammation and remodeling of the vessel wall. Currently, there is a lack of effective pharmacological interventions to prevent aneurysm expansion or rupture, primarily due to insufficient understanding of the molecular mechanisms driving inflammation. Although macrophage infiltration and polarization imbalance are known key factors, the epigenetic mechanisms regulating their phenotypic switching remain unclear. As an enzyme specifically acetylating H4K16, MOF plays a crucial role in immune cell function; however, its specific function and regulatory network in cardiovascular diseases, particularly in AAA, have remained a research gap. This study addresses this mechanistic gap to elucidate how MOF-mediated chromatin modifications determine the pro-inflammatory fate of macrophages.

 

 

Research Methods and Core Experiments

The authors first utilized human and mouse AAA tissue samples combined with single-cell RNA sequencing to identify the MOF gene significantly upregulated in macrophages. To verify causality, the research team constructed two classic mouse models: the angiotensin II-induced model and the elastase-induced model. Key evidence was derived from phenotypic analysis of macrophage-specific MOF knockout mice (Moff/fLyz2Cre+) and pharmacological intervention experiments using the small molecule inhibitor MG-149. Through flow cytometry, chromatin immunoprecipitation (ChIP), and immunofluorescence, the team confirmed that the TNF-α signaling pathway induces MOF expression, which subsequently increases H4K16ac levels in the promoter regions of inflammatory genes, activating NF-κB-mediated transcriptional programs.

Key Conclusions and Perspectives

• MOF is significantly upregulated in macrophages of AAA patients and mouse models, closely associated with the positive regulation of pro-inflammatory gene transcriptional programs.
• Mechanistically, TNF-α stimulation induces MOF expression; MOF promotes the binding and transcriptional activation of NF-κB at the promoter regions of inflammatory genes such as Il1b and Tnfa via acetylation of the H4K16 site.
• In vivo experiments demonstrated that macrophage-specific knockout of MOF or inhibition of its activity using MG-149 significantly reduces elastin degradation and inhibits the formation and expansion of abdominal aortic aneurysms.
• This finding suggests that targeting the MOF-H4K16ac axis is a potential new strategy for intervening in macrophage inflammatory polarization and treating abdominal aortic aneurysms.

Research Significance and Prospects

From a research perspective, this discovery provides a novel epigenetic target for drug development, particularly for the specific regulation of macrophage function. For clinical monitoring, MOF or its downstream markers could serve as biomarkers to assess the risk of AAA progression. Furthermore, the macrophage-specific gene knockout model and pharmacological validation pathway established in this study offer a standardized experimental paradigm for disease modeling and screening anti-inflammatory drugs, potentially driving substantial breakthroughs from basic mechanisms to clinical translation.

 

 

Conclusion

This study deeply elucidates the core driving role of MOF-mediated epigenetic mechanisms in the pathological progression of abdominal aortic aneurysms, filling a critical gap in the macrophage inflammatory regulatory network. By confirming the decisive impact of the TNF-α-MOF-H4K16ac-NF-κB signaling axis in vascular remodeling, this research not only reveals a new mechanism of disease onset but also validates the feasibility of targeting MOF activity inhibition as a therapeutic strategy. From laboratory discovery to clinical translation, this achievement lays a solid theoretical and experimental foundation for developing novel drugs capable of stabilizing the vessel wall and preventing aneurysm rupture, marking a milestone in improving the prognosis and care systems for patients with abdominal aortic aneurysms.

 

Xiaobing He, Nicholas Juriga, Sama Salih, Katherine Gallagher, and Frank M Davis. Acetyltransferase MOF Regulates Macrophage Inflammation in Abdominal Aortic Aneurysms. Circulation research.