Protease-resistant insulin-like growth factor (IGF)-binding protein-4 inhibits IGF-I actions and neointimal expansion in a porcine model of neointimal hyperplasia.

Protease-resistant insulin-like growth factor (IGF)-binding protein-4 inhibits IGF-I actions and neointimal expansion in a porcine model of neointimal hyperplasia. Research Abstract Details 

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Protease-resistant insulin-like growth factor (IGF)-binding protein-4 inhibits IGF-I actions and neointimal expansion in a porcine model of neointimal hyperplasia. Abstract Text:

T C Nichols,W H Busby,E Merricks,J Sipos,M Rowland,K Sitko,D R Clemmons,

IGF-I has been shown to play a role in the progression of atherosclerosis in experimental animal models. IGF-binding protein-4 (IGFBP-4) binds to IGF-I and prevents its association with receptors. Overexpression of a protease-resistant form of IGFBP-4 has been shown to inhibit the ability of IGF-I to stimulate normal smooth muscle cell growth in mice. Based on these observations, we prepared a protease-resistant form of IGFBP-4 and infused it into hypercholesterolemic pigs. Infusion of the protease-resistant mutant inhibited lesion development by 53.3 +/- 6.1% (n = 6; P < 0.01). Control vessels that received an equimolar concentration of IGF-I and the protease-resistant IGFBP-4 showed no reduction in lesion size compared with control lesions that were infused with vehicle. Infusion of a nonmutated form of IGFBP-4 did not significantly inhibit lesion development. Proliferating cell nuclear antigen analysis showed that the mutant IGFBP-4 appeared to inhibit cell proliferation. The area occupied by extracellular matrix was also reduced proportionally compared with total lesion area. Immunoblotting revealed that the mutant IGFBP-4 remained intact, whereas the wild-type IGFBP-4 that was infused was proteolytically cleaved. Further analysis of the lesions revealed that a marker protein, IGFBP-5, whose synthesis is stimulated by IGF-I, was decreased in the lesions that received the protease-resistant, IGFBP-4 mutant, whereas there was no change in lesions that received wild-type IGFBP-4 or the mutant protein plus IGF-I. These findings clearly illustrate that infusion of protease-resistant IGFBP-4 into the perilesion environment results in inhibition of cell proliferation and attenuation of the development of neointima. The findings support the hypothesis that inhibiting IGFBP-4 proteolysis in the lesion microenvironment could be an effective means for regulating neointimal expansion.

Protease-resistant insulin-like growth factor (IGF)-binding protein-4 inhibits IGF-I actions and neointimal expansion in a porcine model of neointimal hyperplasia. Publishing Authors By Initials

TC Nichols,WH Busby,E Merricks,J Sipos,M Rowland,K Sitko,DR Clemmons,

For similar cardiovascular system: blood vessels: endothelium, vascular: tunica intima research abstracts see: cardiovascular system: blood vessels: endothelium, vascular: tunica intima research

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Protease-resistant insulin-like growth factor (IGF)-binding protein-4 inhibits IGF-I actions and neointimal expansion in a porcine model of neointimal hyperplasia. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Endocrinology

VOLUME: 148

Page Numbers: 5002-10

Journal Abbreviation: Endocrinology

ISSN: 0013-7227

DAY: 19

MONTH: 07

YEAR: 2007

Protease-resistant insulin-like growth factor (IGF)-binding protein-4 inhibits IGF-I actions and neointimal expansion in a porcine model of neointimal hyperplasia. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 375040

Protease-resistant insulin-like growth factor (IGF)-binding protein-4 inhibits IGF-I actions and neointimal expansion in a porcine model of neointimal hyperplasia. Keywords Mesh Terms:

KEYWORDS: Tunica Intima

MESH TERMS: pathology

Chemical & Substance for Abstract: Protease-resistant insulin-like growth factor (IGF)-binding protein-4 inhibits IGF-I actions and neointimal expansion in a porcine model of neointimal hyperplasia. Information

Substance Name: Peptide Hydrolases

Registry Number: EC 3.4.-

Grant and Affiliation Information for Protease-resistant insulin-like growth factor (IGF)-binding protein-4 inhibits IGF-I actions and neointimal expansion in a porcine model of neointimal hyperplasia.

AFFILIATION: Division of Endocrinology, University of North Carolina at Chapel Hill, 8024 Burnett-Womack, Chapel Hill, NC 27599-7170, USA.

Country: United States

AGENCY: United States NHLBI

GRANT: HL 56850

ACRONYM: HL

MEDLINETA: Endocrinology

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