Increased Infiltration of Extra-Cardiac Cells in Myxomatous Valve Disease

Sauls, Kimberly; Toomer, Katelynn; Williams, Katherine; Johnson, Amanda J.; Markwald, Roger R.; Hajdu, Zoltán; Norris, Russell A.

doi:10.3390/jcdd2030200

Cited by 26 publications

(39 citation statements)

References 33 publications

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“…Previous studies have shown that inhibition of MEK/2 is a potential therapeutic option for valve disease patients (Sauls et al. ). Taken together, this suggests elastases may be potential markers for early AVD pathogenesis, consistent with our hypothesis that elastic fiber abnormalities play a fundamental role in AVD initiation and progression prior to inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, refametinib or doxycycline treatment significantly decreased the expression of proteolytic enzymes Mmp-9, and cathepsin K and L. Elastic fiber degradation products have shown promise as biomarkers of emerging disease states (Marshall et al 2013). Previous studies have shown that inhibition of MEK/2 is a potential therapeutic option for valve disease patients (Sauls et al 2015). Taken together, this suggests elastases may be potential markers for early AVD pathogenesis, consistent with our hypothesis that elastic fiber abnormalities play a fundamental role in AVD initiation and progression prior to inflammation.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of MAPK‐Erk pathway in vivo attenuates aortic valve disease processes in Emilin1‐deficient mouse model

Munjal

Jegga

Opoka

et al. 2017

Physiological Reports

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Aortic valve disease (AVD) is a common condition with a progressive natural history, and presently, there are no pharmacologic treatment strategies. Elastic fiber fragmentation (EFF) is a hallmark of AVD, and increasing evidence implicates developmental elastic fiber assembly defects. Emilin1 is a glycoprotein necessary for elastic fiber assembly that is present in both developing and mature human and mouse aortic valves. The Emilin1‐deficient mouse (Emilin1 −/−) is a model of latent AVD, characterized by activated TGFβ/MEK/p‐Erk signaling and upregulated elastase activity. Emilin1 −/− aortic valves demonstrate early EFF and aberrant angiogenesis followed by late neovascularization and fibrosis. The objective of this study was to test the effectiveness of three different targeted therapies. Aged (12–14 months) Emilin1 −/− mice were treated with refametinib (RDEA‐119, MEK1/2 inhibitor), doxycycline (elastase inhibitor), or G6‐31 (anti‐VEGF‐A mouse antibody) for 4 weeks. Refametinib‐ and doxycycline‐treated Emilin1 −/− mice markedly reduced MEK/p‐Erk activation in valve tissue. Furthermore, both refametinib and doxycycline attenuated elastolytic cathepsin K, L, MMP‐2, and MMP‐9 activation, and abrogated macrophage and neutrophil infiltration in Emilin1 −/− aortic valves. RNAseq analysis was performed in aortic valve tissue from adult (4 months) and aged (14 months) Emilin1 −/− and age‐matched wild‐type control mice, and demonstrated upregulation of genes associated with MAPK/MEK/p‐Erk signaling and elastases at the adult stage and inflammatory pathways at the aged stage controlling for age. These results suggest that Erk1/2 signaling is an important modulator of early elastase activation, and pharmacological inhibition using refametinib may be a promising treatment to halt AVD progression

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibition of MAPK‐Erk pathway in vivo attenuates aortic valve disease processes in Emilin1‐deficient mouse model

Munjal

Jegga

Opoka

et al. 2017

Physiological Reports

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“…Immunohistochemistry (IHC) was performed as we have previously reported (Norris et al, ; Sauls et al, ; Durst et al, ; Sauls et al, ). Briefly, Mouse fetuses at embryonic day (E) E17.5 were fixed in 4% paraformaldehyde, embedded in paraffin, and sectioned at 5 μm.…”

Section: Methodsmentioning

confidence: 99%

“…As Filamin-A is X-linked in both mouse and humans, we primarily focused our analyses on male mice, although some female mice have been characterized for phenotypic differences. These mice were reported previously by us and others (Feng et al, 2006;Sauls et al, 2012;Gould et al, 2015;Sauls et al, 2015). All mouse experiments were performed under protocols approved by the Institutional Animal Care and Use Committee, Medical University of South Carolina.…”

Section: Materials and Methods Gene-targeted Micementioning

confidence: 99%

“…Due to Filamin-A global knockouts resulting in embryonic lethality by E14.5, we took a conditional approach and genetically removed Filamin-A from endocardium and endocardial derived cells using a Tie2 Cre line. As shown in Figure 1, Tie2 Cre -mediated excision of the floxed-Filamin-A allele resulted in near complete loss of Filamin-A expression in the mitral and tricuspid valve leaflets, consistent with our previous reports Sauls et al, 2015). IHC revealed a near complete loss of R-Ras expression in the mitral and tricuspid valves.…”

Section: R-ras Is Abundantly Expressed In the Valve Leaflets And Is Lmentioning

confidence: 99%

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Filamin‐A as a Balance between Erk/Smad Activities During Cardiac Valve Development

Toomer

Sauls

Fulmer

et al. 2018

The Anatomical Record

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Mitral valve prolapse (MVP) affects 2.4% of the population and has poorly understood etiology. Recent genetic studies have begun to unravel the complexities of MVP and through these efforts, mutations in the FLNA (Filamin-A) gene were identified as disease causing. Our in vivo and in vitro studies have validated these genetic findings and have revealed FLNA as a central regulator of valve morphogenesis. The mechanisms by which FLNA mutations result in myxomatous mitral valve disease are currently unknown, but may involve proteins previously associated with mutated regions of the FLNA protein, such as the small GTPase signaling protein, R-Ras. Herein, we report that filamin-A is required for R-Ras expression and activation of the Ras-Mek-Erk pathway. Loss of the Ras/Erk pathway correlated with hyperactivation of pSmad2/3, increased extracellular matrix (ECM) production and enlarged mitral valves. Analyses of integrin receptors in the mitral valve revealed that Filamin-A was required for beta1 integrin expression and provided a potential mechanism for impaired ECM compaction and valve enlargement. Our data support Filamin-A as a protein that regulates the balance between Erk and Smad activation and an inability of filamin-A deficient valve interstitial cells to effectively remodel the increased ECM production through a beta1-integrin mechanism. As a consequence, loss of filamin-A function results in increased ECM production and generation of a myxomatous phenotype characterized by improperly compacted mitral valve tissue.

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Endothelial Cell Lineage Analysis Does Not Provide Evidence for EMT in Adult Valve Homeostasis and Disease

Kim

Alfieri

Yutzey³

2018

The Anatomical Record

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Epithelial-to-mesenchymal transition (EMT) enables stationary epithelial cells to exhibit migratory behavior and is the key step that initiates heart valve development. Recent studies suggest that EMT is reactivated in the pathogenesis of myxomatous valve disease (MVD), a condition that involves the progressive degeneration and thickening of valve leaflets. These studies have been limited to in vitro experimentation and reliance on histologic co-staining of epithelial and mesenchymal markers as evidence of EMT in mouse and sheep models of valve disease. However, longitudinal analysis of cell lineage origins and potential pathogenic or reparative contributions of newly generated mesenchymal cells have not been reported previously. In this study, a genetic lineage tracing strategy was pursued by irreversibly labeling valve endothelial cells in the Osteogenesis imperfecta and Marfan syndrome mouse models to determine whether they undergo EMT during valve disease. Tie2-CreERT2 and Cdh5(PAC)-CreERT2 mouse lines were used in combination with colorimetric and fluorescent reporters for longitudinal assessment of endothelial cells. These lineage tracing experiments showed no evidence of EMT during adult valve homeostasis or valve pathogenesis. Additionally, CD31 and smooth muscle α-actin (αSMA) double-positive cells, used as an indicator of EMT, were not detected, and levels of EMT transcription factors were not altered. Interestingly, contrary to the endothelial cell-specific Cdh5(PAC)-CreERT2 driver line, Tie2-CreERT2 lineage-derived cells in diseased heart valves also included CD45+ leukocytes. Altogether, our data indicate that EMT is not a feature of valve homeostasis and disease but that increased immune cells may contribute to MVD.

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Increased Infiltration of Extra-Cardiac Cells in Myxomatous Valve Disease

Cited by 26 publications

References 33 publications

Inhibition of MAPK‐Erk pathway in vivo attenuates aortic valve disease processes in Emilin1‐deficient mouse model

Inhibition of MAPK‐Erk pathway in vivo attenuates aortic valve disease processes in Emilin1‐deficient mouse model

Filamin‐A as a Balance between Erk/Smad Activities During Cardiac Valve Development

Endothelial Cell Lineage Analysis Does Not Provide Evidence for EMT in Adult Valve Homeostasis and Disease

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