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, Mingyi Wang, Marjan Gucek, Jing Zhang, James Wu, Liqun Jiang, Robert E. Monticone, Benjamin Khazan, Richard Telljohann, Julie Mattison, Simon Sheng, Robert N. Cole, Gaia Spinetti, Gianfranco Pintus, Lijuan Liu, Frank D. Kolodgie, Renu Virmani, Harold Spurgeon, Donald K. Ingram, Allen D. EverettEdward G. Lakatta, Jennifer Van Eyk

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1337-1346
Number of pages10
JournalCirculation research
Volume104
Issue number12
DOIs
StatePublished - Jun 19 2009

Keywords

  • Aging
  • Angiotensin II
  • MFG-E8
  • Monocyte chemoattractant protein-1
  • Vascular smooth muscle cells

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Fu, Z., Wang, M., Gucek, M., Zhang, J., Wu, J., Jiang, L., Monticone, R. E., Khazan, B., Telljohann, R., Mattison, J., Sheng, S., Cole, R. N., Spinetti, G., Pintus, G., Liu, L., Kolodgie, F. D., Virmani, R., Spurgeon, H., Ingram, D. K., ... Van Eyk, J. (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. Circulation research, 104(12), 1337-1346. https://doi.org/10.1161/CIRCRESAHA.108.187088