© 2001 American Heart Association, Inc.
Vascular Biology |
Insulin-Like Growth Factor Binding Protein-4 Protease Produced by Smooth Muscle Cells Increases in the Coronary Artery After Angioplasty
Presented in part at Endo 2000, Toronto, Canada, June 21–25, 2000.
From the Division of Cardiovascular Diseases (A.B.-G., R.S.S., D.A.L., K.A., D.R.H.) and Endocrine Research Unit (C.A.C.), Mayo Clinic and Foundation, Rochester, Minn; the Institute of Molecular and Structural Biology (M.T.O., C.O.), IMSB, University of Aarhus, Aarhus, Denmark; the Department of Clinical Biochemistry (M.C.), Statens Serum Institute, Aarhus, Denmark.
Correspondence to Robert S. Schwartz, MD, Department of Cardiovascular Diseases, Mayo Clinic, 200 First St, SW, Rochester, MN 55905. E-mail schwartzr{at}mayo.edu
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 (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.
Key Words: insulin-like growth factor • binding protein proteases • restenosis
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