PRAS40 suppresses atherogenesis through inhibition of mTORC1-dependent pro-inflammatory signaling in endothelial cells
Endothelial pro-inflammatory activation plays a pivotal role in atherosclerosis, and many pro-inflammatory and atherogenic signals converge upon mechanistic target of rapamycin (mTOR). Inhibitors of mTOR complex 1 (mTORC1) reduced atherosclerosis in preclinical studies, but side effects including in...
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| Main Authors: | , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
14 November 2019
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| In: |
Scientific reports
Year: 2019, Volume: 9, Pages: 1-13 |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-019-53098-1 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41598-019-53098-1
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| Author Notes: | Kevin Sun Zhang, Johannes Schecker, Alexandros Krull, Eva Riechert, Lonny Juergensen, Verena Kamuf-Schenk, Jana Burghaus, Leon Kiper, Thanh Cao Ho, Kerstin Woeltje, Verena Stangl, Hugo A. Katus, Karl Stangl, Mirko Voelkers & Till F. Althoff |
| Summary: | Endothelial pro-inflammatory activation plays a pivotal role in atherosclerosis, and many pro-inflammatory and atherogenic signals converge upon mechanistic target of rapamycin (mTOR). Inhibitors of mTOR complex 1 (mTORC1) reduced atherosclerosis in preclinical studies, but side effects including insulin resistance and dyslipidemia limit their clinical use in this context. Therefore, we investigated PRAS40, a cell type-specific endogenous modulator of mTORC1, as alternative target. Indeed, we previously found PRAS40 gene therapy to improve metabolic profile; however, its function in endothelial cells and its role in atherosclerosis remain unknown. Here we show that PRAS40 negatively regulates endothelial mTORC1 and pro-inflammatory signaling. Knockdown of PRAS40 in endothelial cells promoted TNF alpha-induced mTORC1 signaling, proliferation, upregulation of inflammatory markers and monocyte recruitment. In contrast, PRAS40-overexpression blocked mTORC1 and all measures of pro-inflammatory signaling. These effects were mimicked by pharmacological mTORC1-inhibition with torin1. In an in vivo model of atherogenic remodeling, mice with induced endothelium-specific PRAS40 deficiency showed enhanced endothelial pro-inflammatory activation as well as increased neointimal hyperplasia and atherosclerotic lesion formation. These data indicate that PRAS40 suppresses atherosclerosis via inhibition of endothelial mTORC1-mediated pro-inflammatory signaling. In conjunction with its favourable effects on metabolic homeostasis, this renders PRAS40 a potential target for the treatment of atherosclerosis. |
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| Item Description: | Gesehen am 06.04.2020 Kevin Sun Zhang and Johannes Schecker contributed equally |
| Physical Description: | Online Resource |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-019-53098-1 |