Osteopontin plays an important role in the development of medial thickening and neointimal formation.
Osteopontin (OPN) is a soluble secreted phosphoprotein that binds with high affinity to several integrins and it has been found at the site of atherosclerotic lesions. However, the role of OPN expression in vivo is still poorly understood. To investigate the physiological role of OPN in detail, we generated transgenic mice (Tg) overexpressing the OPN gene under control of the cytomegalovirus enhancer/chicken beta-actin promoter. We detected OPN mRNAs in almost all tissues of 3 lines of Tg mice by Northern blotting. The serum levels of OPN were significantly higher in Tg than in non-Tg mice (782+/-107 versus 182+/-44 ng/mL; P<0.001). Compared with non-Tg mice, a 73% (88+/-6 versus 51+/-7 microm; P<0.001) and 94% (126+/-15 versus 73+/-11 microm; P<0.0001) increase in the medial thickness of the aorta was determined in Tg mice at 16 and 32 weeks after birth. However, we found no evidence of inflammatory cells adhering to endothelial cells, intimal hyperplasia, or calcification in any region of Tg mice without artery injury. We then investigated the effect of cuff-induced injury to the femoral artery. The intimal thickening in Tg mice increased 2.9-fold more than that in non-Tg mice (4.9+/-1.9 versus 1.7+/-0.4 microm; P=0.022). The expression of OPN induces both medial thickening without injury and neointimal formation after injury, thus suggesting that OPN plays a role in the development of atherosclerosis, vascular remodeling, and restenosis after angioplasty in vivo.
First Department of Internal Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan. isoda@me.ndmc.ac.jp
Kikuo
K
Isoda
Kenichirou
K
Nishikawa
Yashuhiro
Y
Kamezawa
Mikoto
M
Yoshida
Masatoshi
M
Kusuhara
Masao
M
Moroi
Norihiro
N
Tada
Fumitaka
F
Ohsuzu
D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002465:Cell Movement / Q000502:physiology; D005260:Female; D005263:Femoral Artery / Q000293:injuries; D015870:Gene Expression; D007150:Immunohistochemistry; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D053495:Osteopontin; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012795:Sialoglycoproteins / Q000235:genetics / Q000502:physiology*; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D017540:Tunica Media / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*
D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9