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.
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.
Fu
Zongming
Z
Laboratory of Cardiovascular Science, National Institute on Aging-National Institutes of Health, Baltimore, MD 21224, USA.
Wang
Mingyi
M
Gucek
Marjan
M
Zhang
Jing
J
Wu
James
J
Jiang
Liqun
L
Monticone
Robert E
RE
Khazan
Benjamin
B
Telljohann
Richard
R
Mattison
Julie
J
Sheng
Simon
S
Cole
Robert N
RN
Spinetti
Gaia
G
Pintus
Gianfranco
G
Liu
Lijuan
L
Kolodgie
Frank D
FD
Virmani
Renu
R
Spurgeon
Harold
H
Ingram
Donald K
DK
Everett
Allen D
AD
Lakatta
Edward G
EG
Van Eyk
Jennifer E
JE
D000293:Adolescent; D000328:Adult; D000368:Aged; D000375:Aging / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000954:Antigens, Surface / Q000096:biosynthesis* / Q000235:genetics; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D002465:Cell Movement / Q000187:drug effects* / Q000235:genetics; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D020868:Gene Silencing; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D008875:Middle Aged; D008894:Milk Proteins / Q000096:biosynthesis* / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014764:Viral Proteins / Q000494:pharmacology; D037521:Virulence Factors / Q000494:pharmacology
D000954:Antigens, Surface; C414049:CCI protein, Cowpox virus; C111835:CCL2 protein, human; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; C098942:MFGE8 protein, human; C499941:MFGE8 protein, rat; D008894:Milk Proteins; D054390:Receptors, CCR2; D014662:Vasoconstrictor Agents; D014764:Viral Proteins; D037521:Virulence Factors; D000804:Angiotensin II