Published online before print May 14, 2009, doi: 10.1161/CIRCRESAHA.108.187088
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Submitted on September 8, 2008
Revised on April 28, 2009
Accepted on May 4, 2009
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
Zongming Fu ;
From the Department of Medicine (Z.F., S.S., J.E.V.E.); Technical Implementation and Coordination Core (M.G., R.N.C., J.E.V.E.), The Johns Hopkins NHLBI Proteomics Center; Department of Neurology (L.L.); Department of Pediatrics (A.D.E.); Department of Biomedical Engineering (J.E.V.E.); and Department of Biological Chemistry (J.E.V.E.), The Johns Hopkins University, Baltimore, Md; Laboratory of Cardiovascular Science (M.W., L.J., R.E.M., B.K., R.T., H.S., E.G.L.) and Laboratory of Experimental Gerontology (J.M.), National Institute on Aging, NIH, Baltimore, Md; Medstar Research Institute (J.Z., J.W.), Hyattsville, Md; IRCCS MultiMedica (G.S.), Milano, Italy; Department of Biomedical Sciences (G.P.), University of Sassari, Italy; CVPath (F.D.K., R.V.), International Registry of Pathology, Gaithersburg, Md; and Nutritional Neuroscience and Aging Laboratory (D.K.I.), Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge.
* To whom correspondence should be addressed. E-mail: jvaneyk1{at}jhmi.edu.
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.
Key words: MFG-E8 • angiotensin II • monocyte chemoattractant protein-1 • vascular smooth muscle cells • aging