Acetyltransferase MOF Regulates Macrophage Inflammation in Abdominal Aortic Aneurysms

Abstract

BACKGROUND: Abdominal aortic aneurysms (AAAs) are a life-threatening cardiovascular disease for which there is a lack of therapy preventing aortic rupture. During AAA formation, pathological vascular remodeling is driven by an imbalance of proinflammatory and anti-inflammatory macrophage responses, and mechanisms regulating macrophage-mediated inflammation remain undefined. Recent evidence suggests that males absent on the first (MOF), a histone acetyltransferase, can play a critical role in establishing macrophage phenotype and modulating innate immune response. METHODS: Single-cell RNA sequencing analysis of human AAAs and control tissues was performed to analyze MOF expression in aortic monocyte/macrophages and the inflammatory immune response. Mice underwent 2 murine AAA models: either Ang II (angiotensin II) or topical porcine pancreatic elastase. To investigate the role of MOF in AAA development, targeted inhibition was performed with MG-149 administration or in mice genetically deficient in macrophage-specific MOF ( Mof f/f Lyz2 Cre+ ). Finally, flow cytometry and chromatin immunoprecipitation were conducted to analyze macrophage phenotype and levels of histone (H) lysine (K) acetylation (H4K16ac) in human and murine AAA macrophages. RESULTS: Using single-cell RNA sequencing of human AAA tissues and multiple murine AAA models, we identified that MOF is increased in aortic monocyte/macrophages associated with upregulation of inflammatory transcriptional programs. Mechanistically, TNF-α signaling promotes the induction of MOF, which in turn induces NF-κB–mediated inflammatory gene transcription by increasing the activating H4K16ac mark on gene promoters in infiltrating aortic macrophages. In vivo targeted inhibition of the MOF pathway, with myeloid-specific genetic depletion ( Mof f/f Lyz2 Cre+ ) or pharmacological inhibition in the elastase- and angiotensin II–induced AAA model, preserved macrophage function, decreased elastin fragmentation, attenuated aortic inflammation, and markedly reduced AAA development. CONCLUSIONS: Our study provides important evidence that MOF regulates macrophage phenotypic function and inflammation during human and murine AAA development. Targeting the MOF pathway affords the opportunity to prevent pathological macrophage infiltration within the aortic wall and potentially limit AAA development.