Chronic mTOR activation induces a degradative smooth muscle cell phenotype
Chronic mTOR activation induces a degradative smooth muscle cell phenotype
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慢性 mTOR 激活诱导平滑肌细胞退化表型
DOI：
10.1172/jci131048
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发表时间：
2020-03-02
影响因子：
15.9
通讯作者：
Tellides, George
中科院分区：
文献类型：
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作者：
Li, Guangxin;Wang, Mo;Tellides, George
平滑肌细胞（SMC）增殖被认为限制了胸主动脉瘤和夹层（TAAD）的进展，因为中膜细胞的丢失与晚期疾病有关。我们研究了Tsc 1的条件性破坏对主动脉中膜SMC增殖的影响，Tsc 1可过度激活mTOR复合物1。伴随SMC增生导致进行性中膜退变和TAAD。除了减少收缩和合成功能，命运映射SMC显示增加蛋白水解，内吞作用，吞噬作用，和溶酶体清除细胞外基质和凋亡细胞。SMC通过mTOR/β-连环蛋白/MITF依赖性途径通过降解细胞器的生物发生获得有限的巨噬细胞标志物和功能，但与常规巨噬细胞的区别在于缺乏造血谱系标志物和某些免疫效应物，即使在高脂血症的背景下。在由于Fbnl突变的轻度TAAD模型中，类似的mTOR活化和降解SMC表型的诱导大大恶化了疾病，具有几乎一致的致死率。在具有增生和基质降解的临床TAAD标本中，发现中膜SMC中的溶酶体标志物增加，进一步支持了中膜内降解SMC的增殖导致主动脉疾病的概念，从而将mTOR依赖性表型调节确定为对抗TAAD的治疗靶点。
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/beta-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 Fbnl 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.