Human myxomatous mitral valve prolapse: Role of bone morphogenetic protein 4 in valvular interstitial cell activation

Abstract

Myxomatous Mitral valve prolapse (MVP) is the most common cardiac valvular abnormality in industrialized countries and a leading cause of mitral valve surgery for isolated mitral regurgitation. The key role of valvular interstitial cells (VICs) during mitral valve development and homeostasis has been recently suggested, however little is known about the molecular pathways leading to MVP. We aim to characterize Bone Morphogenetic Protein 4 (BMP4) as a cellular regulator of mitral valvular interstitial cell activation towards a pathologic synthetic phenotype and to analyze the cellular phenotypic changes and extracellular matrix (ECM) reorganization associated with the development of myxomatous mitral valve prolapse. Microarray analysis showed significant up regulation of BMP4-mediated signaling molecules in myxomatous MVP when compared to controls. Histological analysis and cellular characterization suggest that during myxomatous MVP development, healthy quiescent mitral VICs undergo a phenotypic activation via up regulation of BMP4-mediated pathway. In vitro hBMP4 treatment of isolated human mitral VICs mimics the cellular activation and ECM remodeling as seen in MVP tissues. The present study characterizes the cell biology of mitral VICs in physiological and pathological conditions and provides insights into the molecular and cellular mechanisms mediated by BMP4 during MVP. The ability to test and control the plasticity of VICs using different molecules may help in developing new diagnostic and therapeutic strategies for myxomatous MVP.

Emerging pathogenic mechanisms in human myxomatous mitral valve: lessons from past and novel data

“…In addition of this canonical pathway, TGF-β signals also through several Smad-independent cascades such as calcium-calcineurin and MAPK pathways. Two almost simultaneous transcriptomic studies comparing myxomatous and control mitral valves revealed, for the first time, an increased expression of TGF-β2 [1] and BMP4 [2] in human MMV. Their significance in the mitral valve disease was further demonstrated by investigating the effect of these growth factors on VIC in vitro.…”

“…Until now, no molecular mechanism was proposed to explain this modification of the VIC phenotype. Recently, we [1] and another research group [2] used global transcriptomic analysis as a start-up to investigate potential pathogenic mechanisms in human idiopathic MMV. These prospective analyses have identified members of the transforming growth factor (TGF)-β superfamily, "a disintegrin and metalloprotease with thrombospondin repeats I" (ADAMTS), and a weakening of the protection against oxidative stress as potential key phases in MMV.…”

Bone Morphogenetic Protein-4 Mediates Cardiac Hypertrophy, Apoptosis, and Fibrosis in Experimentally Pathological Cardiac Hypertrophy

“…A recent work reported that BMP4 was involved in valvular interstitial cell activation in human myxomatous mitral valve prolapse. 21 They found that in vitro hBMP4 treatment of isolated human mitral valvular interstitial cells mimicked the cellular activation and extracellular matrix remodeling as seen in mitral valve prolapse tissues. Mitral valve prolapse was associated with development to progressive mitral regurgitation, which in turn, predisposed to eccentric left ventricular hypertrophy.…”

Contractile Properties of the Right Atrial Myofilaments in Patients with Myxomatous Mitral Valve Degeneration

“…Of course the complexity of cardiac contraction cycle cannot be imaged in a single experimental approach, but it might give some evidence for an affection of myocardial apparatus. We are aware that we examine right atrial tissue and deduce our experimental observation to the right ventricle, but different studies [8,29] prove a similar contractile behavior of atrial and ventricular myofilaments and studies exist about calcium sensitivity in atrial and ventricular skinned cardiac fibers in different cardiac diseases [20], so conclusions seem justified.…”