Affiliation:
1. From the Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY.
Abstract
Objective—
Smooth muscle calponin (
CNN1
) contains multiple conserved intronic CArG elements that bind serum response factor and display enhancer activity in vitro. The objectives here were to evaluate these CArG elements for activity in transgenic mice and determine the effect of human CNN1 on injury-induced vascular remodeling.
Methods and Results—
Mice carrying a lacZ reporter under control of intronic CArG elements in the human
CNN1
gene failed to show smooth muscle cell (SMC)-restricted activity. However, deletion of the orthologous sequences in mice abolished endogenous
Cnn1
promoter activity, suggesting their necessity for in vivo
Cnn1
expression. Mice carrying a 38-kb bacterial artificial chromosome (BAC) harboring the human
CNN1
gene displayed SMC- restricted expression of the corresponding CNN1 protein, as measured by immunohistochemistry and Western blotting. Extensive BAC recombineering studies revealed the absolute necessity of a single intronic CArG element for correct SMC-restricted expression of human CNN1. Overexpressing human CNN1 suppressed neointimal formation following arterial injury. Mice with an identical BAC carrying mutations in CArG elements that inhibit human CNN1 expression showed outward remodeling and neointimal formation.
Conclusion—
A single intronic CArG element is necessary but insufficient for proper CNN1 expression in vivo. CNN1 overexpression antagonizes arterial injury-induced neointimal formation.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine
Cited by
28 articles.
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