Abstract
Objective:
Notch has been implicated in neointima formation as reflected by increased Notch/Jagged expression on vascular injury and the promigratory effect of Notch signaling on smooth muscle cells. Soluble Jagged-1 (sJag1) has been shown to inhibit Notch signaling in vitro; however, its capacity to suppress neointima formation remains unknown.
Methods and results:
Balloon injury of rat carotid arteries induced Notch1, Notch3, and Jagged-1 expression at days 3 and 14 postinjury. Notch signaling was activated as shown by increased expression of the Notch target gene Herp2. Adenoviral sJag1 (Ad-sJag1) transfection reduced neointima formation in carotid artery and enhanced reendothelialization, whereas adenoviral full-length Jagged-1 (Ad-Fl-Jag1) or LacZ had no effect. Injury-induced Herp2 expression was absent in vessels treated with Ad-sJag1. Consistently, Herp2 expression was reduced in Ad-sJag1-infected or recombinant sJag1 -treated coronary artery smooth muscle cells (CASMCs). Ad-sJag1 had no effect on human umbilical endothelial cell behavior, but it significantly reduced proliferation and migration of CASMCs. Overexpression of Herp2 in sJag1-treated CASMCs rescued the migratory and proliferative capacity in vitro.
Conclusions:
Our results demonstrate that sJag1 can inhibit neointima formation after balloon injury by decreasing smooth muscle cell proliferation and migration through interference with Notch-Herp2 signaling.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Analysis of Variance
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Animals
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Basic Helix-Loop-Helix Transcription Factors / metabolism*
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / metabolism*
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Carotid Arteries / metabolism*
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Carotid Arteries / pathology
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Carotid Artery Injuries / genetics
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Carotid Artery Injuries / metabolism
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Carotid Artery Injuries / pathology
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Carotid Artery Injuries / prevention & control*
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Cell Movement
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Cell Proliferation
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Disease Models, Animal
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Endothelial Cells / metabolism
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Endothelial Cells / pathology
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Hyperplasia
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism*
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Jagged-1 Protein
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Muscle, Smooth, Vascular / metabolism
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Muscle, Smooth, Vascular / pathology
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Myocytes, Smooth Muscle / metabolism
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Myocytes, Smooth Muscle / pathology
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Rats
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Rats, Sprague-Dawley
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Receptor, Notch1 / metabolism*
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Receptor, Notch3
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Receptors, Notch / metabolism*
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Repressor Proteins / metabolism*
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Serrate-Jagged Proteins
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Signal Transduction*
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Time Factors
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Transfection
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Tunica Intima / metabolism*
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Tunica Intima / pathology
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Calcium-Binding Proteins
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Hes2 protein, rat
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Intercellular Signaling Peptides and Proteins
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JAG1 protein, human
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Jag1 protein, rat
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Jagged-1 Protein
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Membrane Proteins
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Notch1 protein, rat
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Notch3 protein, rat
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Receptor, Notch1
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Receptor, Notch3
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Receptors, Notch
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Repressor Proteins
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Serrate-Jagged Proteins