Differential activation of valvulogenic, chondrogenic, and osteogenic pathways in mouse models of myxomatous and calcific aortic valve disease. J Mol Cell Cardiol 2012 Mar;52(3):689-700
Date
01/18/2012Pubmed ID
22248532Pubmed Central ID
PMC3294059DOI
10.1016/j.yjmcc.2011.12.013Scopus ID
2-s2.0-84857628377 (requires institutional sign-in at Scopus site) 65 CitationsAbstract
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.
Author List
Cheek JD, Wirrig EE, Alfieri CM, James JF, Yutzey KEMESH terms used to index this publication - Major topics in bold
AnimalsAortic Valve
Calcinosis
Cell Adhesion Molecules
Cell Proliferation
Chondrogenesis
Connective Tissue Cells
Disease Models, Animal
Echocardiography
Glucuronidase
Heart Valve Diseases
Humans
Mice
Mice, Knockout
Osteogenesis
Osteogenesis Imperfecta
Protein Transport
Proteoglycans
Signal Transduction
