Differential activation of valvulogenic, chondrogenic, and osteogenic pathways in mouse models of myxomatous and calcific aortic valve disease
January 17th, 2012 Posted by: admin
Publication year: 2012
Source: Journal of Molecular and Cellular Cardiology, Available online 9 January 2012
Jonathan D. Cheek, Elaine E. Wirrig, Christina M. Alfieri, Jeanne F. James, Katherine E. Yutzey
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 inCol1a2,have distal leaflet thickening and increased proteoglycan composition characteristic of myxomatous valve disease.Periostinnull 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.Klothonull 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/oimmice have increased expression of valve progenitor markersTwist1,Col2a1,Mmp13,Sox9andHapln1, in addition to increasedCol10a1andAsporinexpression, consistent with increased proteoglycan composition.Periostinnull aortic valves exhibit relatively normal gene expression with slightly increased expression ofMmp13andHapln1. In contrast,Klothonull aortic valves have increased expression ofRunx2, consistent with the calcified phenotype, in addition to increased expression ofSox9,Col10a1, andosteopontin. Together these studies demonstrate thatoim/oimmice exhibit histological and molecular characteristics of myxomatous valve disease andKlothonull mice are a new model for calcific aortic valve disease.
Highlights
► Osteogenesis imperfecta mice have myxomatous valve disease. ► Klotho null mice have calcific aortic valve disease without inflammation. ► Mouse models have differential expression of valve progenitor, cartilage and bone genes. ► Myxomatous and calcific valve disease in mice can occur without myofibroblast activation.
