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 and 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.

Multilayer three-dimensional filter paper constructs for the culture and analysis of aortic valvular interstitial cells

“…While positive SMαA expression may not always be necessary for VICs to transition to an osteoblast-like phenotype [10], it is often used to identify VICs undergoing calcification and is found in much higher amounts in diseased aortic valves [31]. Therefore, identification of this marker in 3D VIC cultures is essential.…”

Molecular Mechanisms of Heart Valve Development and Disease

“…End-stage disease is characterized by the presence of calcific nodules at the hinge region of the AoV, underlying the pathology of CAVD [3]. In an effort to draw parallels between the progression of disease and the underlying molecular mechanisms, pediatric and adult diseased AoV were analyzed for markers of valve development and endochondral bone formation [7]. Activated VICs in both pediatric and adult valves have increased expression of valvulogenic markers Twist1, Msx2, and Sox9.…”

“…We have reported that pediatric and adult diseased valves are characterized by expression of markers of valve mesenchymal and chondrogenic progenitor cells, while adult diseased aortic valves express markers of osteogenic calcification [7]. We also have identified novel mouse models of calcific and myxomatous valve disease [8] that will be useful in determination of the underlying mechanisms driving disease and in development of pharmacologic-based therapies.…”

Comparison of Mesenchymal Stem Cell Source Differentiation Toward Human Pediatric Aortic Valve Interstitial Cells within 3D Engineered Matrices

“…25 During aortic valve disease progression, both pediatric and adult diseased aortic valves express markers of chondrogenic cells, while adult diseased aortic valves express more mature osteogenic markers. 26 However, it is unclear what potency pediatric VIC possess, and controlling stable MSC differentiation toward pediatric VIC is important for longterm success of TEHV for pediatric applications.…”