BACKGROUND: Abdominal aortic aneurysm (AAA) is a severe aortic disease with a high mortality rate in the event of rupture. Pharmacological therapy is needed to inhibit AAA expansion and prevent aneurysm rupture. Transcription factor EB (TFEB), a master regulator of autophagy and lysosome biogenesis, is critical to maintain cell homeostasis. In this study, we aim to investigate the role of vascular smooth muscle cell (VSMC) TFEB in the development of AAA and establish TFEB as a novel target to treat AAA. METHODS: The expression of TFEB was measured in human and mouse aortic aneurysm samples. We used loss/gain-of-function approaches to understand the role of TFEB in VSMC survival and explored the underlying mechanisms through transcriptome and functional studies. Using VSMC-selective Tfeb knockout mice and different mouse AAA models, we determined the role of VSMC TFEB and a TFEB activator in AAA in vivo. RESULTS: We found that TFEB is downregulated in both human and mouse aortic aneurysm lesions. TFEB potently inhibits apoptosis in VSMCs, and transcriptome analysis revealed that TFEB regulates apoptotic signaling pathways, especially apoptosis inhibitor B-cell lymphoma 2. B-cell lymphoma 2 is significantly upregulated by TFEB and is required for TFEB to inhibit VSMC apoptosis. We consistently observed that TFEB deficiency increases VSMC apoptosis and promotes AAA formation in different mouse AAA models. Furthermore, we demonstrated that 2-hydroxypropyl-β-cyclodextrin, a clinical agent used to enhance the solubility of drugs, activates TFEB and inhibits AAA formation and progression in mice. Last, we found that 2-hydroxypropyl-β-cyclodextrin inhibits AAA in a VSMC TFEB-dependent manner in mouse models. CONCLUSIONS: Our study demonstrated that TFEB protects against VSMC apoptosis and AAA. TFEB activation by 2-hydroxypropyl-β-cyclodextrin may be a promising therapeutic strategy for the prevention and treatment of AAA.
BACKGROUND: Abdominal aortic aneurysm (AAA) is a severe aortic disease with a high mortality rate in the event of rupture. Pharmacological therapy is needed to inhibit AAA expansion and prevent aneurysm rupture. Transcription factor EB (TFEB), a master regulator of autophagy and lysosome biogenesis, is critical to maintain cell homeostasis. In this study, we aim to investigate the role of vascular smooth muscle cell (VSMC) TFEB in the development of AAA and establish TFEB as a novel target to treat AAA. METHODS: The expression of TFEB was measured in human and mouse aortic aneurysm samples. We used loss/gain-of-function approaches to understand the role of TFEB in VSMC survival and explored the underlying mechanisms through transcriptome and functional studies. Using VSMC-selective Tfeb knockout mice and different mouse AAA models, we determined the role of VSMC TFEB and a TFEB activator in AAA in vivo. RESULTS: We found that TFEB is downregulated in both human and mouse aortic aneurysm lesions. TFEB potently inhibits apoptosis in VSMCs, and transcriptome analysis revealed that TFEB regulates apoptotic signaling pathways, especially apoptosis inhibitor B-cell lymphoma 2. B-cell lymphoma 2 is significantly upregulated by TFEB and is required for TFEB to inhibit VSMC apoptosis. We consistently observed that TFEB deficiency increases VSMC apoptosis and promotes AAA formation in different mouse AAA models. Furthermore, we demonstrated that 2-hydroxypropyl-β-cyclodextrin, a clinical agent used to enhance the solubility of drugs, activates TFEB and inhibits AAA formation and progression in mice. Last, we found that 2-hydroxypropyl-β-cyclodextrin inhibits AAA in a VSMC TFEB-dependent manner in mouse models. CONCLUSIONS: Our study demonstrated that TFEB protects against VSMC apoptosis and AAA. TFEB activation by 2-hydroxypropyl-β-cyclodextrin may be a promising therapeutic strategy for the prevention and treatment of AAA.
Authors: Chensu Wang; Hanspeter Niederstrasser; Peter M Douglas; Rueyling Lin; Juan Jaramillo; Yang Li; Nathaniel W Oswald; Anwu Zhou; Elizabeth A McMillan; Saurabh Mendiratta; Zhaohui Wang; Tian Zhao; Zhiqaing Lin; Min Luo; Gang Huang; Rolf A Brekken; Bruce A Posner; John B MacMillan; Jinming Gao; Michael A White Journal: Nat Commun Date: 2017-12-22 Impact factor: 14.919
Authors: Judit Váradi; Anca Hermenean; Rudolf Gesztelyi; Viktória Jeney; Enikő Balogh; László Majoros; Milo Malanga; Éva Fenyvesi; Lajos Szente; Ildikó Bácskay; Miklós Vecsernyés; Pálma Fehér; Zoltán Ujhelyi; Gábor Vasvári; István Árvai; Ágnes Rusznyák; Cornel Balta; Hildegard Herman; Ferenc Fenyvesi Journal: Biomolecules Date: 2019-09-20
Authors: Tanmoy Roychowdhury; Haocheng Lu; Whitney E Hornsby; Bradley Crone; Gao T Wang; Dong-Chuan Guo; Anoop K Sendamarai; Poornima Devineni; Maoxuan Lin; Wei Zhou; Sarah E Graham; Brooke N Wolford; Ida Surakka; Zhenguo Wang; Lin Chang; Jifeng Zhang; Michael Mathis; Chad M Brummett; Tori L Melendez; Michael J Shea; Karen Meekyong Kim; G Michael Deeb; Himanshu J Patel; Jonathan Eliason; Kim A Eagle; Bo Yang; Santhi K Ganesh; Ben Brumpton; Bjørn Olav Åsvold; Anne Heidi Skogholt; Kristian Hveem; Saiju Pyarajan; Derek Klarin; Philip S Tsao; Scott M Damrauer; Suzanne M Leal; Dianna M Milewicz; Y Eugene Chen; Minerva T Garcia-Barrio; Cristen J Willer Journal: Am J Hum Genet Date: 2021-07-14 Impact factor: 11.025