Expression of the cysteine protease legumain in vascular lesions and functional implications in atherogenesis.
OBJECTIVE
The present study was conducted to characterize the expression of the cysteine protease legumain in murine and human atherosclerotic tissues, and to explore the molecular mechanisms by which legumain may contribute to the pathophysiology of atherosclerosis.


RESULTS
Using microarray analysis, legumain mRNA expression was found to increase with development of atherosclerosis in the aorta of aging Apolipoprotein E deficient mice while expression remained at low level and unchanged in arteries of age-matched C57BL/6 control mice. In situ hybridization and immunohistochemical analysis determined that legumain was predominantly expressed by macrophages in the atherosclerotic aorta, in lesions at the aortic sinus and in injured carotid arteries of Apolipoprotein E deficient mice as well as in inflamed areas in advanced human coronary atherosclerotic plaques. In vitro, M-CSF differentiated human primary macrophages were shown to express legumain and the protein could also be detected in the culture media. When tested in migration assays, legumain induced chemotaxis of primary human monocytes and human umbilical vein endothelial cells.


CONCLUSIONS
Legumain is expressed in both murine and human atherosclerotic lesions. The macrophage-specific expression of legumain in vivo and ability of legumain to induce chemotaxis of monocytes and endothelial cells in vitro suggest that legumain may play a functional role in atherogenesis.
Clerin
Valerie
V
Department of Cardiovascular and Metabolic Diseases, Wyeth Research, 200 CambridgePark Drive, Cambridge, MA 02140, USA. vclerin@wyeth.com
Shih
Heather H
HH
Deng
Nanhua
N
Hebert
Gustave
G
Resmini
Christine
C
Shields
Kathleen M
KM
Feldman
Jeffrey L
JL
Winkler
Aaron
A
Albert
Leo
L
Maganti
Vasu
V
Wong
Anthony
A
Paulsen
Janet E
JE
Keith
James C
JC
Vlasuk
George P
GP
Pittman
Debra D
DD
D000367:Age Factors; D000818:Animals; D001018:Aortic Diseases / Q000201:enzymology* / Q000209:etiology* / Q000503:physiopathology; D001057:Apolipoproteins E / Q000502:physiology; D050197:Atherosclerosis / Q000201:enzymology* / Q000209:etiology* / Q000503:physiopathology; D003546:Cysteine Endopeptidases / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000502:physiology; D005260:Female; D006801:Humans; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D000099240:Asparaginyl Endopeptidase
D001057:Apolipoproteins E; D003546:Cysteine Endopeptidases; D012333:RNA, Messenger; D000099240:Asparaginyl Endopeptidase