Milk fat globule protein epidermal growth factor-8: a pivotal relay element within the angiotensin II and monocyte chemoattractant protein-1 signaling cascade mediating vascular smooth muscle cells invasion.
Milk fat globule protein epidermal growth factor-8: a pivotal relay element within the angiotensin II and monocyte chemoattractant protein-1 signaling cascade mediating vascular smooth muscle cells invasion.
复制标题
牛奶脂肪球蛋白表皮生长因子-8：血管紧张素II和单核细胞趋化剂蛋白-1信号传导级联血管平滑肌细胞侵入的关键继电器元件。
DOI：
10.1161/circresaha.108.187088
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发表时间：
2009-06-19
影响因子：
20.1
通讯作者：
Van Eyk JE
中科院分区：
文献类型：
--
作者：
Fu Z;Wang M;Gucek M;Zhang J;Wu J;Jiang L;Monticone RE;Khazan B;Telljohann R;Mattison J;Sheng S;Cole RN;Spinetti G;Pintus G;Liu L;Kolodgie FD;Virmani R;Spurgeon H;Ingram DK;Everett AD;Lakatta EG;Van Eyk JE
增龄导致主动脉壁增厚，这是多种信号蛋白协同作用的结果，其中许多信号蛋白尚不清楚。为了寻找与主动脉壁增厚相关的新蛋白质，我们进行了一项全面的定量蛋白质组学研究，分析了年轻(8个月)和老年(30个月)大鼠的主动脉蛋白质，鉴定出50个随着年龄增长而显著变化的蛋白质。一种新的蛋白质，乳脂球蛋白表皮生长因子8(MFG-E8)，在老年主动脉中的丰度增加了2.3倍。转录和翻译分析表明，在包括人类在内的几种哺乳动物中，主动脉MFG-E8的mRNA和蛋白水平随着年龄的增长而增加。双重免疫标记显示，MFG-E8与血管紧张素II(Ang II)和单核细胞趋化蛋白-1(MCP-1)共存于增厚的老年主动脉壁的血管平滑肌细胞(VSMCs)内。将幼年大鼠主动脉早期传代的VSMSC暴露于Ang II可显著增加MFG-E8，并增强老年大鼠VSMCs的侵袭能力。MFG-E8处理VSMCs可增加MCP-1的表达和VSMCs的侵袭力，而MCP-1受体阻滞剂VCCI可抑制MCP-1表达和VSMCs侵袭。沉默MFG-E8 RNA可显著降低MFG-E8的表达和VSMCs的侵袭能力。结果表明，动脉MFG-E8随增龄而显着增加，是Ang II/MCP-1/VSMC侵袭信号级联中的关键传递元件。因此，在该信号轴通路中靶向MFG-E8是预防和治疗动脉粥样硬化等与年龄相关的血管疾病的潜在新疗法。
Advancing age induces aortic wall thickening that results from the concerted effects of numerous signaling proteins, many of which have yet to be identified. To search for novel proteins associated with aortic wall thickening, we have performed a comprehensive quantitative proteomic study to analyze aortic proteins from young (8 mo) and old (30 mo) rats and identified 50 proteins that significantly change in abundance with aging. One novel protein, the milk fat globule protein epidermal growth factor 8 (MFG-E8), increases 2.3-fold in abundance in old aorta. Transcription and translation analysis demonstrated that aortic MFG-E8 mRNA and protein levels increase with aging in several mammalian species including humans. Dual immunolabeling shows that MFG-E8 colocalizes with both angiotensin II (Ang II) and monocyte chemoattractant protein-1 (MCP-1) within vascular smooth muscle cells (VSMCs) of the thickened aged aortic wall. Exposure of early passage VMSCs from young aorta to Ang II markedly increases MFG-E8 and enhances invasive capacity to levels observed in VSMCs from old rats. Treatment of VSMCs with MFG-E8 increases MCP-1 expression and VSMCs invasion that are inhibited by the MCP-1 receptor blocker, vCCI. Silencing MFG-E8 RNA substantially reduces MFG-E8 expression and VSMCs invasion capacity. The data indicate that arterial MFG-E8 significantly increases with aging and is a pivotal relay element within the Ang II/MCP-1/VSMC invasion signaling cascade. Thus, targeting of MFG-E8 within this signaling axis pathway is a potential novel therapy for the prevention and treatment of the age-associated vascular diseases such as atherosclerosis.