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

被引：80

作者：

Fu, Zongming ^{[1
]}

Wang, Mingyi ^{[6
]}

Gucek, Marjan ^{[13
]}

Zhang, Jing ^{[8
]}

Wu, James ^{[8
]}

Jiang, Liqun ^{[6
]}

Monticone, Robert E. ^{[6
]}

Khazan, Benjamin ^{[6
]}

Telljohann, Richard ^{[6
]}

Mattison, Julie ^{[7
]}

Sheng, Simon ^{[1
]}

Cole, Robert N. ^{[13
]}

Spinetti, Gaia ^{[9
]}

Pintus, Gianfranco ^{[10
]}

Liu, Lijuan ^{[2
]}

Kolodgie, Frank D. ^{[11
]}

Virmani, Renu ^{[11
]}

Spurgeon, Harold ^{[6
]}

Ingram, Donald K. ^{[12
]}

Everett, Allen D. ^{[3
]}

Lakatta, Edward G. ^{[6
]}

Van Eyk, Jennifer E. ^{[1
,4
,5
,13
]}

机构：

[1] Johns Hopkins Univ, Dept Med, Baltimore, MD USA

[2] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA

[3] Johns Hopkins Univ, Dept Pediat, Baltimore, MD 21218 USA

[4] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD USA

[5] Johns Hopkins Univ, Dept Biol Chem, Baltimore, MD USA

[6] NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA

[7] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA

[8] Medstar Res Inst, Hyattsville, MD USA

[9] IRCCS MultiMed, Milan, Italy

[10] Univ Sassari, Dept Biomed Sci, I-07100 Sassari, Italy

[11] Int Registry Pathol, CVPath, Gaithersburg, MD USA

[12] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Nutr Neurosci & Aging Lab, Baton Rouge, LA USA

[13] Johns Hopkins Univ, Johns Hopkins Bayview Prote Ctr, Baltimore, MD USA

来源：

CIRCULATION RESEARCH | 2009年 / 104卷 / 12期

关键词：

MFG-E8; angiotensin II; monocyte chemoattractant protein-1; vascular smooth muscle cells; aging; CARDIOVASCULAR-DISEASE ENTERPRISES; CYSTEINE-RICH PROTEIN-2; TRANSGENIC MOUSE MODEL; STE20-LIKE KINASE SLK; AGE-RELATED-CHANGES; GENE-EXPRESSION; TGF-BETA; GEL-ELECTROPHORESIS; MAJOR SHAREHOLDERS; PROTEOMIC ANALYSIS;

D O I：

10.1161/CIRCRESAHA.108.187088

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 months) and old (30 months) 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 and monocyte chemoattractant protein (MCP)-1 within vascular smooth muscle cells (VSMCs) of the thickened aged aortic wall. Exposure of early passage VSMCs from young aorta to angiotensin 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 angiotensin 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. (Circ Res. 2009; 104: 1337-1346.)

引用

页码：1337 / 1346

页数：10

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