PMID- 31728028 OWN - NLM STAT- MEDLINE DCOM- 20201102 LR - 20210110 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 9 IP - 1 DP - 2019 Nov 14 TI - PRAS40 suppresses atherogenesis through inhibition of mTORC1-dependent pro-inflammatory signaling in endothelial cells. PG - 16787 LID - 10.1038/s41598-019-53098-1 [doi] LID - 16787 AB - 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 TNFalpha-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. FAU - Zhang, Kevin Sun AU - Zhang KS AD - Department of Cardiology, Angiology, and Pneumology, University Hospital Heidelberg, University of Heidelberg, Heidelberg, Germany. AD - DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany. FAU - Schecker, Johannes AU - Schecker J AD - Charite - University Medicine Berlin, Department of Cardiology and Angiology, Charite Campus Mitte, Berlin, Germany. AD - DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany. FAU - Krull, Alexandros AU - Krull A AD - Charite - University Medicine Berlin, Department of Cardiology and Angiology, Charite Campus Mitte, Berlin, Germany. AD - DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany. FAU - Riechert, Eva AU - Riechert E AUID- ORCID: 0000-0003-4876-7860 AD - Department of Cardiology, Angiology, and Pneumology, University Hospital Heidelberg, University of Heidelberg, Heidelberg, Germany. AD - DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany. FAU - Jurgensen, Lonny AU - Jurgensen L AD - Department of Cardiology, Angiology, and Pneumology, University Hospital Heidelberg, University of Heidelberg, Heidelberg, Germany. AD - DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany. FAU - Kamuf-Schenk, Verena AU - Kamuf-Schenk V AD - Department of Cardiology, Angiology, and Pneumology, University Hospital Heidelberg, University of Heidelberg, Heidelberg, Germany. AD - DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany. FAU - Burghaus, Jana AU - Burghaus J AD - Department of Cardiology, Angiology, and Pneumology, University Hospital Heidelberg, University of Heidelberg, Heidelberg, Germany. AD - DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany. FAU - Kiper, Leon AU - Kiper L AD - Department of Cardiology, Angiology, and Pneumology, University Hospital Heidelberg, University of Heidelberg, Heidelberg, Germany. AD - DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany. FAU - Cao Ho, Thanh AU - Cao Ho T AD - Department of Cardiology, Angiology, and Pneumology, University Hospital Heidelberg, University of Heidelberg, Heidelberg, Germany. AD - DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany. FAU - Woltje, Kerstin AU - Woltje K AD - Charite - University Medicine Berlin, Department of Cardiology and Angiology, Charite Campus Mitte, Berlin, Germany. AD - DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany. FAU - Stangl, Verena AU - Stangl V AD - Charite - University Medicine Berlin, Department of Cardiology and Angiology, Charite Campus Mitte, Berlin, Germany. AD - DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany. FAU - Katus, Hugo A AU - Katus HA AD - Department of Cardiology, Angiology, and Pneumology, University Hospital Heidelberg, University of Heidelberg, Heidelberg, Germany. AD - DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany. FAU - Stangl, Karl AU - Stangl K AD - Charite - University Medicine Berlin, Department of Cardiology and Angiology, Charite Campus Mitte, Berlin, Germany. AD - DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany. FAU - Volkers, Mirko AU - Volkers M AUID- ORCID: 0000-0003-2344-1856 AD - Department of Cardiology, Angiology, and Pneumology, University Hospital Heidelberg, University of Heidelberg, Heidelberg, Germany. mirko.voelkers@med.uni-heidelberg.de. AD - DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany. mirko.voelkers@med.uni-heidelberg.de. FAU - Althoff, Till F AU - Althoff TF AD - Charite - University Medicine Berlin, Department of Cardiology and Angiology, Charite Campus Mitte, Berlin, Germany. till.althoff@charite.de. AD - DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany. till.althoff@charite.de. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20191114 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - 0 (AKT1S1 protein, human) RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (TNF protein, human) RN - 0 (Tumor Necrosis Factor-alpha) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) SB - IM MH - Adaptor Proteins, Signal Transducing/*genetics/metabolism MH - Animals MH - Atherosclerosis/genetics/immunology/*pathology MH - Cell Proliferation MH - Disease Models, Animal MH - Endothelial Cells/metabolism MH - Gain of Function Mutation MH - Gene Knockout Techniques MH - Human Umbilical Vein Endothelial Cells MH - Humans MH - Loss of Function Mutation MH - Mechanistic Target of Rapamycin Complex 1/*metabolism MH - Mice MH - Signal Transduction MH - Tumor Necrosis Factor-alpha/*metabolism PMC - PMC6856095 COIS- The authors declare no competing interests. EDAT- 2019/11/16 06:00 MHDA- 2020/11/03 06:00 PMCR- 2019/11/14 CRDT- 2019/11/16 06:00 PHST- 2019/03/21 00:00 [received] PHST- 2019/10/21 00:00 [accepted] PHST- 2019/11/16 06:00 [entrez] PHST- 2019/11/16 06:00 [pubmed] PHST- 2020/11/03 06:00 [medline] PHST- 2019/11/14 00:00 [pmc-release] AID - 10.1038/s41598-019-53098-1 [pii] AID - 53098 [pii] AID - 10.1038/s41598-019-53098-1 [doi] PST - epublish SO - Sci Rep. 2019 Nov 14;9(1):16787. doi: 10.1038/s41598-019-53098-1.