Abstract 129: BAF60c Prevents Abdominal Aortic Aneurysm Formation Through Maintaining Vascular Smooth Muscle Cell Homeostasis

Abstract

Background: Abdominal aortic aneurysm (AAA) is a common and life-threatening vascular disease. Vascular smooth muscle cell (VSMC) dysfunction is involved in the dilatation and eventual rupture of AAA, with the precise epigenetic control of this process less studied. BAF60c, a unique subunit of SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, serves as a core modulator of physiological and pathological processes, yet little is known about its function in the vasculature and pathogenesis of AAA. Methods and Results: BAF60c is downregulated in AAAs from humans and mice with primary staining to the aortic VSMC, confirmed by single cell RNA sequencing. In vivo studies revealed that VSMC-specific knockout Baf60c markedly aggravated both AngII- and elastase-induced murine AAA formation, with significant increases of elastin degradation, inflammatory cell accumulation, VSMC phenotype switching, and apoptosis. In vitro studies showed that knockdown of BAF60c in human aortic smooth muscle cells resulted in the loss of contractile phenotype while upregulation of inflammatory genes and increased apoptosis. Chromatin immunoprecipitation followed by sequencing and qPCR, as well as CoIP assays showed that BAF60c maintained VSMC contractile phenotype by enhancing serum response factor association with its co-activator p300 and SWI/SNF complex, suppressed VSMC inflammation via precise control of the repressive state of NF-κB-target genes, as well as prevented VSMC apoptosis through transcriptional activation of KLF5-dependent BCL2 expression. Conclusions: Our study indicates that BAF60c is essential for SWI/SNF complex recruitment to chromatin and interaction with diverse transcription factors to precise epigenetic control of VSMC homeostasis and prevention of AAA formation.