PRAS40 suppresses atherogenesis through inhibition of mTORC1-dependent pro-inflammatory signaling in endothelial cells

• Verfasst von: Zhang, Kevin Sun [VerfasserIn]
• Verfasst von: Schecker, Johannes [VerfasserIn]
• Verfasst von: Riechert, Eva [VerfasserIn]
• Verfasst von: Jürgensen, Lonny [VerfasserIn]
• Verfasst von: Burghaus-Zhang, Jana [VerfasserIn]
• Verfasst von: Katus, Hugo [VerfasserIn]
• Verfasst von: Völkers, Mirko [VerfasserIn]
• Titel: PRAS40 suppresses atherogenesis through inhibition of mTORC1-dependent pro-inflammatory signaling in endothelial cells
• Verf.angabe: 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
• E-Jahr: 2019
• Jahr: 14 November 2019
• Umfang: 13 S.
• Fussnoten: Gesehen am 06.04.2020 ; Kevin Sun Zhang and Johannes Schecker contributed equally
• Titel Quelle: Enthalten in: Scientific reports
• Ort Quelle: [London] : Macmillan Publishers Limited, part of Springer Nature, 2011
• Jahr Quelle: 2019
• Band/Heft Quelle: 9(2019) Artikel-Nummer 16787, 13 Seiten
• ISSN Quelle: 2045-2322
• DOI: doi:10.1038/s41598-019-53098-1
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: atherosclerosis
• Sach-SW: disease
• Sach-SW: expression
• Sach-SW: mammalian target
• Sach-SW: mice
• Sach-SW: mtor inhibition
• Sach-SW: pathway
• Sach-SW: rapamycin
• Sach-SW: risk
• Sach-SW: sirolimus
• K10plus-PPN: 1694107493

Abstract

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.