Enhanced autophagy in GAB1-deficient vascular endothelia cells is responsible for atherosclerosis progression
Enhanced autophagy in GAB1-deficient vascular endothelia cells is responsible for atherosclerosis progression
复制标题
GAB1缺陷的血管内皮细胞自噬增强是动脉粥样硬化进展的原因
作者：
Xin Qian;Han Wang;Yuli Wang;Jiaquan Chen;Xiangjiang Guo;Haoyu Deng
自噬对细胞健康至关重要，其功能障碍与包括动脉粥样硬化在内的许多人类疾病的发病机制有关。随着动脉粥样硬化的进展，自噬可以去除坏死细胞并延缓斑块的发展。然而，在某些类型的缺血期间发生的高水平自噬可以触发自体，导致不可避免的细胞死亡。Grb2相关结合蛋白1(GAB1)是一种对接/支架连接蛋白，调节包括自噬在内的许多细胞过程。我们的研究首次报道了GAB1蛋白在外周动脉疾病(PAD)中的表达显著降低。在机制方面，我们的结果表明，抑制mTOR的上游Akt通过下调p62蛋白的表达和上调Lc3II/Lc3I的比例显著上调自噬。相反，我们发现抑制ERK1/2、p38和JNK通过上调p62蛋白表达和下调LC3II/LC3I比值显著下调自噬。此外，GAB1的敲除通过包括ERK1/2、p38和JNK在内的MAPK通路显著增加了HUVEC的自噬。此外，我们还发现GAB1基因的敲除显著抑制了HUVECs的迁移和管状结构的形成。综上所述，这项研究首次表明GAB1是HUVEC自噬的关键调节因子。
Autophagy is paramount to cellular health and its dysfunction is implicated in the pathogenesis of many human diseases which includes atherosclerosis. As atherosclerosis progresses, autophagy can remove necrotic cells and delay development of the plaque. However, high-level autophagy, as occurs during certain types of ischemia can trigger autosis, leading to inevitable cellular demise. Grb2-associated binder 1 (GAB1) is a docking/ scaffolding adaptor protein that regulates many cell processes including autophagy. Our study first reported that the protein expression of GAB1 significantly decreased in peripheral artery diseases(PAD). In terms of mechanism, our results showed that inhibition of Akt, the upstream of mTOR, significantly upregulates autophagy by demonstrating the downregulation of p62 protein expression and the upregulation of the ratio of LC3II/LC3I. Conversely, we demonstrated that inhibition of ERK1/2, p38 and JNK significantly downregulates autophagy by demonstrating the upregulation of p62 protein expression and the downregulation of the ratio of LC3II/LC3I. Further, knockdown of GAB1 significantly increased autophagy in HUVECs via MAPK pathways that includes ERK1/2, p38 and JNK. Moreover, we found that knockdown of GAB1 profoundly inhibits HUVECs migration and tube formation. Taken together, this study first suggested that GAB1 is a key regulator of autophagy in HUVECs.