Chronic mTOR activation induces a degradative smooth muscle cell phenotype
| العنوان: | Chronic mTOR activation induces a degradative smooth muscle cell phenotype |
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| المؤلفون: | Jay D. Humphrey, Nicholas A. Cilfone, Mo Wang, Pei-Yu Chen, Bo Jiang, George Tellides, Arina Korneva, Arnar Geirsson, Jeffrey R. Gulcher, Lingfeng Qin, Guilin Wang, Sameet Mehta, Michael Simons, Thomas Chittenden, Yang Jiao, Alexander W. Caulk, Matthew R. Bersi, Guangxin Li, Zehua Chen, Chang-Shun He, Sameh Yousef, Xinran Liu, Sharvari Gujja |
| المصدر: | J Clin Invest |
| بيانات النشر: | American Society for Clinical Investigation, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Mice, Knockout, ApoE, Phagocytosis, Myocytes, Smooth Muscle, Cell, Context (language use), Mechanistic Target of Rapamycin Complex 1, Biology, Endocytosis, Tuberous Sclerosis Complex 1 Protein, Extracellular matrix, Mice, 03 medical and health sciences, 0302 clinical medicine, medicine, Animals, Macrophage, Aorta, beta Catenin, PI3K/AKT/mTOR pathway, Microphthalmia-Associated Transcription Factor, Aortic Aneurysm, Thoracic, TOR Serine-Threonine Kinases, General Medicine, Hyperplasia, medicine.disease, Cell biology, Aortic Dissection, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Commentary, cardiovascular system, Lysosomes, Signal Transduction |
| الوصف: | Smooth muscle cell (SMC) proliferation has been thought to limit the progression of thoracic aortic aneurysm and dissection (TAAD) because loss of medial cells associates with advanced disease. We investigated effects of SMC proliferation in the aortic media by conditional disruption of Tsc1, which hyperactivates mTOR complex 1. Consequent SMC hyperplasia led to progressive medial degeneration and TAAD. In addition to diminished contractile and synthetic functions, fate-mapped SMCs displayed increased proteolysis, endocytosis, phagocytosis, and lysosomal clearance of extracellular matrix and apoptotic cells. SMCs acquired a limited repertoire of macrophage markers and functions via biogenesis of degradative organelles through an mTOR/β-catenin/MITF-dependent pathway, but were distinguishable from conventional macrophages by an absence of hematopoietic lineage markers and certain immune effectors even in the context of hyperlipidemia. Similar mTOR activation and induction of a degradative SMC phenotype in a model of mild TAAD due to Fbn1 mutation greatly worsened disease with near-uniform lethality. The finding of increased lysosomal markers in medial SMCs from clinical TAAD specimens with hyperplasia and matrix degradation further supports the concept that proliferation of degradative SMCs within the media causes aortic disease, thus identifying mTOR-dependent phenotypic modulation as a therapeutic target for combating TAAD. |
| تدمد: | 1558-8238 0021-9738 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::76639387fc3989f0bff964c81b8fa24f https://doi.org/10.1172/jci131048 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....76639387fc3989f0bff964c81b8fa24f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15588238 00219738 |
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