BRG1 Ablation in Vascular Smooth Muscle Cells Ameliorates Abdominal Aortic Aneurysm: Mechanism and Translational...

Abdominal aortic aneurysm (AAA) is a major vascular pathology with high morbidity and mortality. Phenotypic changes of vascular smooth muscle cells (VSMC) play a key role in AAA pathogenesis. In the present study, we investigated the effect of VSMC-specific ablation of BRG1, a chromatin remodeling protein, on AAA pathogenesis focusing on transcriptional mechanism and translational potential. BRG1 expression was elevated in VSMCs by pro-AAA stimuli in vitro and in vivo. Compared to the BRG1^f/f mice, the VSMC-specific BRG1 knockout mice (BRG1^ΔSMC) displayed a less severe AAA phenotype induced by chronic angiotensin II (Ang II) infusion, by treatment with calcium phosphate, or by treatment with porcine pancreatic elastase as evidenced by smaller vascular dilation, decreased rupture of elastic fiber, decreased VSMC apoptosis, and reduced MMP activities. BRG1 deletion significantly attenuated the induction of apoptosis and MMP activities by Ang II treatment in cultured VSMCs. RNA-seq uncovered Cathepsin K (Ctsk) as a novel transcriptional target for BRG1 in VSMCs. Ang II stimulated Ctsk expression in VSMCs whereas Brg1 deletion repressed Ctsk induction. BRG1 was detected to directly bind to the Ctsk promoter to activate transcription. Consistently, Ctsk knockdown in VSMCs dampened apoptosis and inhibited MMP activities. Finally, inhibition of BRG1 activity with a small-molecule compound (PFI-3) ameliorated phenotypic modulation in VSMCs and mitigated AAA in mice. Our data suggest that BRG1 may contribute to AAA pathogenesis by activating Ctsk transcription in VSMCs. Therefore, targeting BRG1 can be considered as a reasonable approach for AAA intervention.