The Role of Transforming Growth Factor-β Signaling in Myxomatous Mitral Valve Degeneration

Abstract

Mitral valve prolapse (MVP) due to myxomatous degeneration is one of the most important chronic degenerative cardiovascular diseases in people and dogs. It is a common cause of heart failure leading to significant morbidity and mortality in both species. Human MVP is usually classified into primary or non-syndromic, including Barlow’s Disease (BD), fibro-elastic deficiency (FED) and Filamin-A mutation, and secondary or syndromic forms (typically familial), such as Marfan syndrome (MFS), Ehlers-Danlos syndrome, and Loeys–Dietz syndrome. Despite different etiologies the diseased valves share pathological features consistent with myxomatous degeneration. To reflect this common pathology the condition is often called myxomatous mitral valve degeneration (disease) (MMVD) and this term is universally used to describe the analogous condition in the dog. MMVD in both species is characterized by leaflet thickening and deformity, disorganized extracellular matrix, increased transformation of the quiescent valve interstitial cell (qVICs) to an activated state (aVICs), also known as activated myofibroblasts. Significant alterations in these cellular activities contribute to the initiation and progression of MMVD due to the increased expression of transforming growth factor-β (TGF-β) superfamily cytokines and the dysregulation of the TGF-β signaling pathways. Further understanding the molecular mechanisms of MMVD is needed to identify pharmacological manipulation strategies of the signaling pathway that might regulate VIC differentiation and so control the disease onset and development. This review briefly summarizes current understanding of the histopathology, cellular activities, molecular mechanisms and pathogenesis of MMVD in dogs and humans, and in more detail reviews the evidence for the role of TGF-β.

Pro-Inflammatory and Immunological Profile of Dogs with Myxomatous Mitral Valve Disease

“…In fact, TGF-β triggers the endothelial-to-mesenchymal transition, which in turn leads to the phenotypic differentiation of the valve interstitial cells (VICs) in their active form, which are ultimately responsible for the degrading of the extracellular matrix (ECM) which is expressed with the typical morphostructural changes. It is noteworthy to underline that the activation of VICs is also associated with an increase in Il-1β production, which, in turn, negatively affects the ECM [ 35 ].…”

Genetics and pathophysiology of mitral valve prolapse

“…Monocytes are established actors of tissue homeostasis, wound repair and disease. Although MVP was considered as non-inflammatory disease for a long time ( 88 ), CD45 + hematopoietic cells have been reported in human, sheep ( 89 , 90 ) and murine ( 42 , 72 , 87 , 91 ) myxomatous MVP. Most recent study by Kim et al demonstrated the dominant role of monocyte-derived macrophages and the associated pro-inflammatory environment in the development of myxomatous MV dystrophy ( 42 , 87 ) in a mouse model of Marfan syndrome.…”

Mitral valve transcriptome analysis in thirty-four age-matched Cavalier King Charles Spaniels with or without myxomatous mitral valve disease

“…Abundance of myxomatous effector proteins has previously been shown to increase in response to increased tensile strain on the heart valves (Lacerda et al 2012;Orton et al 2012). TGFβsignaling and disturbances in ECM organization have also been suggested as primary causes of MMVD (reviewed by Tang et al 2022). However, the present results, i.e., the apparent well-orchestrated expression of genes related to these pathways, encourage us to suggest that these pathways were upregulated as a well-regulated compensatory mechanism to MMVD in ~ 10 years old dogs with no/early MMVD.…”