Insulin-like growth factor binding protein-4 protease produced by smooth muscle cells increases in the coronary artery after angioplasty.
Insulin-like growth factor (IGF)-I stimulates vascular smooth muscle cell (VSMC) migration and proliferation, which are fundamental to neointimal hyperplasia in postangioplasty restenosis. IGF-I action is modulated by several high-affinity IGF binding proteins (IGFBPs). IGFBP-4 is the predominant IGFBP produced by VSMCs and is a potent inhibitor of IGF-I action. However, specific IGFBP-4 proteases can cleave IGFBP-4 and liberate active IGF-I. In this study, we document IGFBP-4 protease produced by human and porcine coronary artery VSMCs in culture as pregnancy-associated plasma protein-A (PAPP-A). This was shown by a distinctive IGFBP-4 cleavage pattern, specific inhibition of IGFBP-4 protease activity with PAPP-A polyclonal antibodies, and immunorecognition of PAPP-A by monoclonal antibodies. Furthermore, we found a 2-fold increase in IGFBP-4 protease activity in injured porcine VSMC cultures in vitro (P<0.05). We also evaluated IGFBP-4 protease/PAPP-A expression in vivo after coronary artery balloon injury. Twenty-five immature female pigs underwent coronary overstretch balloon injury, and vessels were examined at defined time points after the procedure. Abundant PAPP-A expression was observed in the cytoplasm of medial and neointimal cells 7, 14, and 28 days after angioplasty (P<0.01 vs control). The highest PAPP-A labeling indices were located in the neointima (36.1+/-2.1%) and the media (31.7+/-1.2%) 28 days after injury. Western blot analysis confirmed increased PAPP-A in injured vessels. PAPP-A, a regulator of IGF-I bioavailability through proteolysis of IGFBP-4, is thus expressed by VSMCs in vitro and in restenotic lesions in vivo. These results suggest a possible role for PAPP-A in neointimal hyperplasia.
Division of Cardiovascular Diseases, Mayo Clinic and Foundation, Rochester, Minnesota, USA.
A
A
Bayes-Genis
R S
RS
Schwartz
D A
DA
Lewis
M T
MT
Overgaard
M
M
Christiansen
C
C
Oxvig
K
K
Ashai
D R
DR
Holmes
C A
CA
Conover
D000328:Adult; D000800:Angioplasty, Balloon; D000818:Animals; D002478:Cells, Cultured; D003327:Coronary Disease / Q000378:metabolism* / Q000628:therapy; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011266:Pregnancy-Associated Plasma Protein-A / Q000378:metabolism; D013552:Swine
D007335:Insulin-Like Growth Factor II; D008666:Metalloendopeptidases; D011266:Pregnancy-Associated Plasma Protein-A