Expression of parathyroid hormone-related protein in human and experimental atherosclerotic lesions: functional role in arterial intimal thickening.
We investigated the expression of parathyroid hormone-related protein (PTHrP) in atherosclerotic lesions and the role of PTHrP in the development of arterial neointima formation. Immunohistochemical staining of PTHrP in the neointima of rat aorta produced by balloon injury and of rat femoral artery produced by non-obstructive polyethylene cuff placement, and in the atherosclerotic lesion of human coronary artery was performed using anti-human PTHrP-(1-34) antibody. Anti-muscle actin antibody, HHF-35, and anti-macrophage antibody, HAM-56, were used to identify smooth muscle cells and macrophages, respectively. Immunoreactivity of PTHrP was detected in the thickened intima of rat and human lesions where the predominant cell types were smooth muscle cells or macrophages dependently on the lesion type. In the next series of experiments, we examined the effect of PTHrP on the development of cuff-induced intimal thickening of rat femoral artery. Either PTHrP-(1-34) or PTHrP-(7-34), a PTH/PTHrP receptor antagonist, suspended in pluronic F-127 gel was locally applied around the rat femoral artery. Intimal thickening induced by cuff placement was evaluated 2 weeks later. PTHrP-(1-34) dose-dependently inhibited intimal thickening determined as intima/media ratio and % stenosis whereas PTHrP-(7-34) dose-dependently enhanced that. These results suggest that PTHrP, which is expressed in atherosclerotic lesions, inhibits the development of neointimal formation.
Ishikawa
M
M
Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-8655, Tokyo, Japan.
Akishita
M
M
Kozaki
K
K
Toba
K
K
Namiki
A
A
Yamaguchi
T
T
Orimo
H
H
Ouchi
Y
Y
D000704:Analysis of Variance; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000473:pathology; D001158:Arteries / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D003324:Coronary Artery Disease / Q000378:metabolism*; D003331:Coronary Vessels / Q000187:drug effects / Q000473:pathology; D046508:Culture Techniques; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005263:Femoral Artery / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments / Q000008:administration & dosage / Q000378:metabolism*; D011336:Probability; D011506:Proteins / Q000008:administration & dosage / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values; D013045:Species Specificity; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology*
D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D011506:Proteins; C054296:parathyroid hormone-related protein (1-34)