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

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• 作者：Jonathan D. Cheek¹ ; Elaine E. Wirrig¹ ; Christina M. Alfieri ; Jeanne F. James ; Katherine E. Yutzey ; ^{katherine.yutzey@cchmc.org}
• 关键词：CAVD ; Calcific aortic valve disease ; BAV ; Bicuspid aortic valve ; OI ; Osteogenesis imperfecta ; pHH3 ; Phospho-histone H3 ; SMA ; Smooth muscle 伪-actin ; ECM ; Extracellular matrix ; VIC ; Valve interstitial cell
• 刊名：Journal of Molecular and Cellular Cardiology
• 出版年：2012
• 期刊代码：171_00222828
• 类别：bio
• 出版时间：March, 2012
• 卷：52
• 期：3
• 页码：689-700
• 文件大小：3919 K

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. m>Osteogenesis imperfecta murinem> (m>Oimm>) mice, with a mutation in m>Col1a2m>, have distal leaflet thickening and increased proteoglycan composition characteristic of myxomatous valve disease. m>Periostinm> 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. m>Klothom> 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. m>Oim/oimm> mice have increased expression of valve progenitor markers m>Twist1m>, m>Col2a1m>, m>Mmp13m>, m>Sox9m> and m>Hapln1m>, in addition to increased m>Col10a1m> and m>Asporinm> expression, consistent with increased proteoglycan composition. m>Periostinm> null aortic valves exhibit relatively normal gene expression with slightly increased expression of m>Mmp13m> and m>Hapln1m>. In contrast, m>Klothom> null aortic valves have increased expression of m>Runx2m>, consistent with the calcified phenotype, in addition to increased expression of m>Sox9m>, m>Col10a1m>, and m>osteopontinm>. Together these studies demonstrate that m>oim/oimm> mice exhibit histological and molecular characteristics of myxomatous valve disease and m>Klothom> null mice are a new model for calcific aortic valve disease.