Insulin-Like Growth Factor Binding Protein-4 Protease Produced by Smooth Muscle Cells Increases in the Coronary Artery After Angioplasty

Abstract

Abstract-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 (PϽ0.05). 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 (PϽ0.01 vs control). The highest PAPP-A labeling indices were located in the neointima (36.1Ϯ2.1%) and the media (

Pregnancy associated plasma protein-A (PAPP-A) as an early marker for the diagnosis of acute coronary syndrome

“…These were in agreement with Bayes-Genis et al 7 who observed increased PAPP-A concentrations even in patients with negative cardiac troponin. Pregnancy associated plasma protein-A appeared to be an independent predictor of future ischaemic events as well as the need for percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery.…”

Pregnancy‐associated plasma protein‐A (PAPP‐A) expression and insulin‐like growth factor binding protein‐4 protease activity in normal and malignant ovarian surface epithelial cells

“…8,9,40,41 In this role, PAPP-A cleaves IGFBP-4 and reduces its affinity for IGFs, effectively increasing local IGF bioavailability. Similar to the observation of increased PAPP-A expression in healing human skin 42 and during vascular repair, 14,15 this could be a mechanism by which PAPP-A induces the proliferation of OSE cells after ovulation and subsequent repair of the ovulation-associated wound.…”

“…12,13 In addition, PAPP-A activation is implicated in injury-repair responses in the vasculature through local increases in bioavailable IGF. 14,15 In spite of its clinical importance, the study of OSE has been limited because of the difficulty in obtaining the cells from rou-tinely handled surgical samples, the small numbers of cells retrieved and the limited lifespan of OSE cells in culture (reviewed in reference 16). To overcome technical limitations, we built upon the work of Dr. N. Auersperg whose laboratory optimized the culture of OSE and transformation by SV40LT, generating IOSE cells.…”

Activity of ulilysin, an archaeal PAPP-A-related gelatinase and IGFBP protease

“…For this protein, which is also found in mammals, specific IGF-independent cleavage of IGFBP-5 identical to PAPP-A and partial activity against IGFBP-3 have been reported (Farr et al, 2000;Bayes-Genis et al, 2001b;Overgaard et al, 2001). These pappalysins contain the sequence motif His-GluXxx-Xxx-His-Xxx-Xxx-Gly-Xxx-Xxx-His/Asp (Xxx for any residue), a zinc-binding consensus sequence (ZBCS) that is the hallmark of the metzincin clan of MPs.…”