title: Differential expression of cartilage and bone-related proteins in pediatric and adult diseased aortic valves.
abstract: Approximately 5 million people are affected with aortic valve disease (AoVD) in the United States. The most common treatment is aortic valve (AoV) replacement surgery, however, replacement valves are susceptible to failure, necessitating additional surgeries. The molecular mechanisms underlying disease progression and late AoV calcification are not well understood. Recent studies suggest that genes involved in bone and cartilage development play an active role in osteogenic-like calcification in human calcific AoVD (CAVD). In an effort to define the molecular pathways involved in AoVD progression and calcification, expression of markers of valve mesenchymal progenitors, chondrogenic precursors, and osteogenic differentiation was compared in pediatric non-calcified and adult calcified AoV specimens. Valvular interstitial cell (VIC) activation, extracellular matrix (ECM) disorganization, and markers of valve mesenchymal and skeletal chondrogenic progenitor cells were observed in both pediatric and adult AoVD. However, activated BMP signaling, increased expression of cartilage and bone-type collagens, and increased expression of the osteogenic marker Runx2 are observed in adult diseased AoVs. They are not observed in the majority of pediatric diseased valves, representing a marked distinction in the molecular profile between pediatric and adult diseased AoVs. The combined evidence suggests that an actively regulated osteochondrogenic disease process underlies the pathological changes affecting AoVD progression, ultimately resulting in stenotic AoVD. Both pediatric and adult diseased AoVs express protein markers of valve mesenchymal and chondrogenic progenitor cells while adult diseased AoVs also express proteins involved in osteogenic calcification. These findings provide specific molecular indicators of AoVD progression, which may lead to identification of early disease markers and the development of potential therapeutics.
authors.affiliation: Division of Molecular Cardiovascular Biology, The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Elaine E
authors.initials: EE
authors.lastname: Wirrig
authors.forename: Robert B
authors.initials: RB
authors.lastname: Hinton
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Yutzey
mesh_terms: D000368:Aged; D001021:Aortic Valve / Q000378:metabolism* / Q000473:pathology*; D015415:Biomarkers / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D001842:Bone and Bones / Q000378:metabolism* / Q000473:pathology; D002114:Calcinosis / Q000235:genetics / Q000473:pathology; D002356:Cartilage / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D020219:Chondrogenesis / Q000235:genetics / Q000502:physiology; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000096:biosynthesis / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism; D006349:Heart Valve Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D026161:MADS Domain Proteins / Q000096:biosynthesis / Q000235:genetics; D064326:MEF2 Transcription Factors; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D018006:Myogenic Regulatory Factors / Q000096:biosynthesis / Q000235:genetics; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
chemical_list: D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578040:MEF2C protein, human; D018006:Myogenic Regulatory Factors; C493709:RUNX2 protein, human; D014157:Transcription Factors; D003094:Collagen