Abstract 707: Vascular Smooth Muscle Cell Tfeb Deletion Promotes Abdominal Aortic Aneurysms

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 38; no. Suppl_1
• Main Authors: Lu, Haocheng, Fan, Yanbo, Liang, Wenying, Hu, Wenting, Xiong, Wenhao, Chang, Ziyi, Garcia-Barrio, Minerva, Zhang, Jifeng, Chen, Yuqing
• Format: Journal Article
• Language: English
• Published: 01.05.2018
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/atvb.38.suppl_1.707

Abstract only Rationale: Abdominal aortic aneurysm (AAA) is a vascular disease with a very high mortality rate in the case of rupture. Vascular smooth muscle cells (VSMCs) are crucial to maintaining vascular integrity and function. Transcription Factor EB (TFEB) is a master regulator of autophagy and lysosomal biogenesis in a variety of cell types via inducing the transcription of a coordinated lysosomal regulatory gene network. TFEB shows anti-inflammatory and anti-atherosclerotic effects in vascular endothelial cells and macrophages. However, the role of TFEB in vascular disease remains to be further explored. Objectives: To investigate the role of VSMC TFEB in AAA. Methods and Results: We found that TFEB was down-regulated in human aortic aneurysmal lesion compared with the non-lesion area by QRT-PCR and immunostaining. In human aortic smooth muscle cells (HASMCs), TFEB mRNA and protein abundance were decreased upon treatment with pro-inflammatory factors while adenovirus-mediated TFEB overexpression potently inhibits inflammation, apoptosis (caspase 3 cleavage and Annexin V staining) and matrix metalloproteinase activity (zymography). A consistent phenotype was observed in the TFEB knockdown HASMCs. Mechanistically, TFEB activates the PI3K-Akt pathway, and PI3K inhibitors (wortmannin and LY294002) abolished the anti-apoptotic effect of TFEB in HASMCs. Utilizing VSMC-specific TFEB deficiency mice (floxed-TFEB/myh11-ERT2 cre+), we determined the effect of TFEB on AAA formation in vivo. In the mouse aneurysm model induced by the combination of angiotensin II and 3-aminopropionitrile infusion, TFEB VSMC-deletion significantly increases aneurysm formation, rupture, and mortality (n =13-14 for each group, p< 0.01). Conclusions: Our data reveal a critical protective role of TFEB in VSMC homeostasis, suggesting TFEB to be a potential target to treat aortic aneurysm.