The Role of Transcription Factor EB in the Vascular Wall Biology
Lu, Haocheng
2019
Abstract
Transcription factor EB (TFEB) is a member of the microphthalmia transcription factor family, with adjacent basic helix-loop-helix and leucine zipper domains. Among them, TFEB has been found to be a master regulator of autophagy and lysosome biogenesis. TFEB is implicated in lysosomal storage diseases and neurodegenerative diseases. However, the role of TFEB in vascular biology is poorly understood. In this study, we aim to explore the role of TFEB and underlying mechanisms in vascular diseases. Growing evidence suggests that endothelial cell dysfunction occurs in the initial stage of atherogenesis. Laminar shear stress, which protects against atherosclerosis, increased TFEB abundance in cultured primary human endothelial cells. The locations with a higher laminar shear stress of the rabbit aorta also show higher expression of TFEB. Furthermore, TFEB overexpression in endothelial cells (ECs) suppressed adhesion molecule and inflammatory cytokine expression., whereas TFEB knockdown aggravated adhesion molecule and inflammatory cytokine expression. TFEB knockdown also diminished the effect of laminar shear stress to suppress adhesion molecule and inflammatory cytokine expression in ECs, indicating TFEB to be a mediator of the anti-inflammatory and anti-atherosclerotic effects of laminar shear stress. The anti-inflammatory effect of TFEB was, at least, partially due to reduced oxidative stress because TFEB overexpression in endothelial cells decreased the concentrations of reactive oxygen species and increased the expression of the antioxidant genes HO1 (which encodes heme oxygenase 1) and SOD2 (which encodes superoxide dismutase 2). Chromatin immunoprecipitation (ChIP) assay and luciferase reporter assay indicated that TFEB directly bound to the promoter of HO1 and SOD2. To study the EC TFEB function in vivo, we generated mTie2-TFEB transgenic mice, in which TFEB was overexpressed in ECs. The transgenic mice exhibited reduced leukocyte recruitment to endothelial cells and decreased atherosclerosis development in ApoE-/- background. Abdominal aortic aneurysm (AAA) has a very high mortality rate in the event of rupture. It would be of high significance to identify novel strategies to prevent or treat AAA. We found that TFEB expression is reduced in the human aneurysm lesion. Both gain- and loss-of-function experiments demonstrated that TFEB inhibited the apoptosis of human aortic smooth muscle cells (HASMCs). Mechanistic studies showed that TFEB upregulated B-cell lymphoma 2 (BCL2) and BCL2 inhibitor abolishes the anti-apoptotic effect of TFEB. ChIP and luciferase reporter assays indicated that TFEB directly bound to the promoter of BCL2, suggesting BCL2 is a direct target of TFEB. To determine the role of TFEB in AAA in vivo, we utilized smooth muscle cell (SMC)- specific Tfeb knockout (KO) mice and applied two different mouse AAA models: β-aminopropionitrile/Angiotensin II- and PCSK9/Angiotensin II-induced murine aneurysm models. Consistent results were observed in the two AAA models, in which TFEB deficiency increases SMC apoptosis and promotes AAA formation. Of significance, we demonstrated that TFEB activator, 2-hydroxypropyl-β-cyclodextrin (HPβCD), attenuates aneurysm formation and inhibits HASMC apoptosis in the PCSK9/Angiotensin II model. Using SMC-TFEB KO mice, we further demonstrated that vascular smooth muscle cell (VSMC) TFEB is essential for the inhibitory effects of HPβCD on AAA formation and VSMC apoptosis in vivo. Our study suggests that TFEB regulates important biological functions in the vascular wall including ECs and VSMCs. As a transcription factor, TFEB directly increases the transcription of anti-oxidant and anti-apoptotic genes. TFEB constitutes a molecular target for the treatment or prevention of vascular diseases such as atherosclerosis and aortic aneurysms.Subjects
Transcription factor EB Endothelial inflammation Atherosclerosis Vascular smooth muscle cell apoptosis Aneurysm
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