Lysyl oxidase propeptide inhibits smooth muscle cell signaling and proliferation.
Lysyl oxidase is required for the normal biosynthesis and maturation of collagen and elastin. It is expressed by vascular smooth muscle cells, and its increased expression has been previously found in atherosclerosis and in models of balloon angioplasty. The lysyl oxidase propeptide (LOX-PP) has more recently been found to have biological activity as a tumor suppressor, and it inhibits Erk1/2 Map kinase activation. We reasoned that LOX-PP may have functions in normal non-transformed cells. We, therefore, investigated its effects on smooth muscle cells, focusing on important biological processes mediated by Erk1/2-dependent signaling pathways including proliferation and matrix metalloproteinase-9 (MMP-9) expression. In addition, we investigated whether evidence for accumulation of LOX-PP could be found in vivo in a femoral artery injury model. Recombinant LOX-PP was expressed and purified, and was found to inhibit primary rat aorta smooth muscle cell proliferation and DNA synthesis by more than 50%. TNF-alpha-stimulated MMP-9 expression and Erk1/2 activation were both significantly inhibited by LOX-PP. Immunohistochemistry studies carried out with affinity purified anti-LOX-PP antibody showed that LOX-PP epitopes were expressed at elevated levels in vascular lesions of injured arteries. These novel data suggest that LOX-PP may provide a feedback control mechanism that serves to inhibit properties associated with the development of vascular pathology.
Department of Periodontology and Oral Biology, Boston University Goldman School of Dental Medicine, Division of Oral Biology, 700 Albany Street, W-210 Boston, MA 02118, USA.
Paola A
PA
Hurtado
Siddharth
S
Vora
Siddika Selva
SS
Sume
Dan
D
Yang
Cynthia
C
St Hilaire
Ying
Y
Guo
Amitha H
AH
Palamakumbura
Barbara M
BM
Schreiber
Katya
K
Ravid
Philip C
PC
Trackman
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010455:Peptides / Q000008:administration & dosage*; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D010455:Peptides; D008249:Protein-Lysine 6-Oxidase