Differential protein expression between normal, early‐stage, and late‐stage myxomatous mitral valves from dogs

Abstract

Valvular heart disease accounts for over 20 000 deaths and 90 000 hospitalizations yearly in the United States. Myxomatous valve disease (MVD) is the most common disease of the mitral valve in humans and dogs. MVD is pathologically identical in these species and its pathogenesis is poorly understood. The objectives of this study were to (i) develop proteomic methodology suitable for analysis of extracellular matrix-rich heart valve tissues and (ii) survey over- and under-expressed proteins that could provide mechanistic clues into the pathogenesis of MVD. Normal, early-stage, and late-stage myxomatous mitral valves from dogs were studied. A shotgun proteomic analysis was used to quantify differential protein expression. Proteins were classified by function and clustered according to differential expression patterns. More than 300 proteins, with 117 of those being differentially expressed, were identified. Hierarchical sample clustering of differential protein profiles showed that early- and late-stage valves were closely related. This finding suggests that proteome changes occur in early degeneration stages and these persist in late stages, characterizing a diseased proteome that is distinct from normal. Shotgun proteome analysis of matrix-rich canine heart valves is feasible, and should be applicable to human heart valves. This study provides a basis for future investigations into the pathogenesis of MVD.

Gene network and canonical pathway analysis in canine myxomatous mitral valve disease: A microarray study

“…Nevertheless, the role of CHAD and KERA in the mitral valve is unknown. In a canine MMVD proteomic study, decorin and biglycan were found to be up-regulated at the early stage of MMVD, but down-regulated at the late stage (Lacerda et al, 2009). In contrast in human MMVD, biglycan (protein), decorin (both mRNA and protein), and versican (protein) were found more abundantly expressed compared with normal mitral valves (Radermecker et al, 2003;Gupta et al, 2009).…”

“…Myxomatous mitral valve disease (MMVD) is the single most common acquired heart disease of the dog and is characterised by endothelial damage, stromal matrix degeneration, interstitial cell proliferation in the sub-endothelial zone and interstitial cell phenotypic changes (Buchanan, 1977;Beardow and Buchanan, 1993;Corcoran et al, 2004;Black et al, 2005;Disatian et al, 2008;Han et al, 2008;Lacerda et al, 2009;Borgarelli and Buchanan, 2012). The end-stage disease results in significant mitral regurgitation that can lead to left-sided congestive heart failure (Häggström et al, 2009).…”

“…While much is known about the structural and cellular changes in canine MMVD, less is known about the molecular mechanisms and biochemical changes (Richards et al, 2012). Limited proteomic and transcriptomic data are available but have provided interesting insights into disease pathogenesis, for example, the role of serotonin (5-hydroxytryptamine or 5-HT) in MMVD (Oyama and Chittur, 2006;Lacerda et al, 2009). …”

Unravelling the proteome of degenerative human mitral valves

“…Several proteoglycans (e.g., decorin, biglycan, and mimecan) and cell adhesion proteins (e.g., versican, talin, and fibronectin) were found to be regulated in degenerated canine mitral valves, which suggests that extracellular remodeling occurs in the course of myxomatous transformation . Decorin, biglycan, and versican have also been associated with remodeling of other matrix components in myxomatous human mitral valves .…”

“…Thus this proteome database would contribute to a better understanding of the underlying disease biology, and may provide new insights for the diagnosis and therapy of DMVD. associated with valve degeneration in dogs [6], but to our knowledge, studies on the human mitral valve proteome have not been published. In part, the immediate procurement and preservation of mitral valve tissue during corrective mitral surgery poses logistical challenges and tissue samples have become less available as conservative surgery is increasingly adopted [7,8].…”