Differential activation of valvulogenic, chondrogenic, and osteogenic pathways in mouse models of myxomatous and calcific aortic valve disease

被引:60
|
作者
Cheek, Jonathan D. [1 ]
Wirrig, Elaine E. [1 ]
Alfieri, Christina M. [1 ]
James, Jeanne F. [1 ]
Yutzey, Katherine E. [1 ]
机构
[1] Cincinnati Childrens Hosp Med Ctr, Inst Heart, Cincinnati, OH 45229 USA
关键词
Aortic valve disease; Valvular interstitial cells; Calcification; Extracellular matrix; Mouse models of human disease; HEART-VALVE; PERIOSTIN; STENOSIS; CARTILAGE; MICE; EXPRESSION; CELLS; PROGRESSION; MUTATION; FETUS;
D O I
10.1016/j.yjmcc.2011.12.013
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Studies of human diseased aortic valves have demonstrated increased expression of genetic markers of valve progenitors and osteogenic differentiation associated with pathogenesis. Three potential mouse models of valve disease were examined for cellular pathology, morphology, and induction of valvulogenic, chondrogenic, and osteogenic markers. Osteogenesis imperfecta murine (Oim) mice, with a mutation in Col1a2, have distal leaflet thickening and increased proteoglycan composition characteristic of myxomatous valve disease. Periostin null mice also exhibit dysregulation of the ECM with thickening in the aortic midvalve region, but do not have an overall increase in valve leaflet surface area. Klotho null mice are a model for premature aging and exhibit calcific nodules in the aortic valve hinge-region, but do not exhibit leaflet thickening. ECM disorganization, or inflammation. Oim/oim mice have increased expression of valve progenitor markers Twist1, Col2a1, Mmp13, Sox9 and Hapln1, in addition to increased Col10a1 and Asporin expression, consistent with increased proteoglycan composition. Periostin null aortic valves exhibit relatively normal gene expression with slightly increased expression of Mmp13 and Hapln1. In contrast, Klotho null aortic valves have increased expression of Runx2, consistent with the calcified phenotype, in addition to increased expression of Sox9, Col10a1, and osteopontin. Together these studies demonstrate that oim/oim mice exhibit histological and molecular characteristics of myxomatous valve disease and Klotho null mice are a new model for calcific aortic valve disease. (C) 2012 Elsevier Ltd. All rights reserved.
引用
收藏
页码:689 / 700
页数:12
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