Dataset Information

Developmental basis for filamin-A-associated myxomatous mitral valve disease.

ABSTRACT:

Aims

We hypothesized that the structure and function of the mature valves is largely dependent upon how these tissues are built during development, and defects in how the valves are built can lead to the pathological progression of a disease phenotype. Thus, we sought to uncover potential developmental origins and mechanistic underpinnings causal to myxomatous mitral valve disease. We focus on how filamin-A, a cytoskeletal binding protein with strong links to human myxomatous valve disease, can function as a regulatory interface to control proper mitral valve development.

Methods and results

Filamin-A-deficient mice exhibit abnormally enlarged mitral valves during foetal life, which progresses to a myxomatous phenotype by 2 months of age. Through expression studies, in silico modelling, 3D morphometry, biochemical studies, and 3D matrix assays, we demonstrate that the inception of the valve disease occurs during foetal life and can be attributed, in part, to a deficiency of interstitial cells to efficiently organize the extracellular matrix (ECM). This ECM organization during foetal valve gestation is due, in part, to molecular interactions between filamin-A, serotonin, and the cross-linking enzyme, transglutaminase-2 (TG2). Pharmacological and genetic perturbations that inhibit serotonin-TG2-filamin-A interactions lead to impaired ECM remodelling and engender progression to a myxomatous valve phenotype.

Conclusions

These findings illustrate a molecular mechanism by which valve interstitial cells, through a serotonin, TG, and filamin-A pathway, regulate matrix organization during foetal valve development. Additionally, these data indicate that disrupting key regulatory interactions during valve development can set the stage for the generation of postnatal myxomatous valve disease.

SUBMITTER: Sauls K

PROVIDER: S-EPMC3444235 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Publications

Developmental basis for filamin-A-associated myxomatous mitral valve disease.

Sauls Kimberly K de Vlaming Annemarieke A Harris Brett S BS Williams Katherine K Wessels Andy A Levine Robert A RA Slaugenhaupt Susan A SA Goodwin Richard L RL Pavone Luigi Michele LM Merot Jean J Schott Jean-Jacques JJ Le Tourneau Thierry T Dix Thomas T Jesinkey Sean S Feng Yuanyi Y Walsh Christopher C Zhou Bin B Baldwin Scott S Markwald Roger R RR Norris Russell A RA

Cardiovascular research 20120725 1

<h4>Aims</h4>We hypothesized that the structure and function of the mature valves is largely dependent upon how these tissues are built during development, and defects in how the valves are built can lead to the pathological progression of a disease phenotype. Thus, we sought to uncover potential developmental origins and mechanistic underpinnings causal to myxomatous mitral valve disease. We focus on how filamin-A, a cytoskeletal binding protein with strong links to human myxomatous valve disea ...[more]

PMID: 22843703

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Project description:Myxomatous mitral valve disease (MMVD) is the most common acquired canine cardiovascular disease and shares many similarities with human mitral valvulopathies. While transcriptomic datasets are available for the end-stage disease in both species, there is no information on how gene expression changes as the disease progresses, such that it cannot be stated with certainty if the changes seen in end-stage disease are casual or consequential. In contrast to humans, the disease in dogs can be more readily examined as it progresses, and this allows an opportunity for insight into disease pathogenesis relevant to both species. The aim of this study was to identify changes in valve gene expression as canine MMVD advances over an entire life-time, from normal (grade 0) to severely affected (grade 4), and differences in gene expression comparing normal and disease areas of the same valve. Transcriptomic profiling identified 1002 differentially expressed genes (DEGs) across all four disease grades when compared with normal valves with the greatest number of DEGs in grade 3 (673) and grade 4 (507). DEGs were associated with a large number of gene families, including genes encoding cytoskeletal filaments, peptidases, extra-cellular matrix (ECM) proteins, chemokines and integrins. Gene enrichment analysis identified significant grade-dependent changes in gene clustering, with clusters trending both up and down as disease progressed. Significant grade-dependent changes in hallmark disease gene expression intensity were identified, including ACTA2, HTR2B, MMP12, and CDKN2A. Gene Ontology terms were dominated by terms for ECM and inflammation with TGF?1, TNF, IFGN identified as the top up-stream regulators in both whole and dissected diseased valve samples. These data show that while disease progression in MMVD is associated with increasing numbers of DEGs, TGF? appears to be the dominant signaling pathway controlling pathogenesis irrespective of disease severity.

Project description:BackgroundMitral annular disjunction (MAD) consists of an altered spatial relation between the left atrial wall, the attachment of the mitral leaflets, and the top of the left ventricular (LV) free wall, manifested as a wide separation between the atrial wall-mitral valve junction and the top of the LV free wall. Originally described in association with myxomatous mitral valve disease, this abnormality was recently revisited by a surgical group that pointed its relevance for mitral valve reparability. The aims of this study were to investigate the echocardiographic prevalence of mitral annular disjunction in patients with myxomatous mitral valve disease, and to characterize the clinical profile and echocardiographic features of these patients.MethodsWe evaluated 38 patients with myxomatous mitral valve disease (mean age 57 ± 15 years; 18 females) and used standard transthoracic echocardiography for measuring the MAD. Mitral annular function, assessed by end-diastolic and end-systolic annular diameters, was compared between patients with and without MAD. We compared the incidence of arrhythmias in a subset of 21 patients studied with 24-hour Holter monitoring.ResultsMAD was present in 21 (55%) patients (mean length: 7.4 ± 8.7 mm), and was more common in women (61% vs 38% in men; p = 0.047). MAD patients more frequently presented chest pain (43% vs 12% in the absence of MAD; p = 0.07). Mitral annular function was significantly impaired in patients with MAD in whom the mitral annular diameter was paradoxically larger in systole than in diastole: the diastolic-to-systolic mitral annular diameter difference was -4,6 ± 4,7 mm in these patients vs 3,4 ± 1,1 mm in those without MAD (p < 0.001). The severity of MAD significantly correlated with the occurrence of non-sustained ventricular tachycardia (NSVT) on Holter monitoring: MAD›8.5 mm was a strong predictor for (NSVT), (area under ROC curve = 0.74 (95% CI, 0.5-0.9); sensitivity 67%, specificity 83%). There were no differences between groups regarding functional class, severity of mitral regurgitation, LV volumes, and LV systolic function.ConclusionsMAD is a common finding in myxomatous mitral valve disease patients, easily recognizable by transthoracic echocardiography. It is more prevalent in women and often associated with chest pain. MAD significantly disturbs mitral annular function and when severe predicts the occurrence of NSVT.

Project description:Canine myxomatous mitral valve disease (MMVD) is similar to Barlow's form of MMVD in humans. These valvulopathies are complex, with varying speeds of progression. We hypothesized that the relative abundances of serum proteins would help identify the consecutive MMVD stages and discover new disease pathways on a systemic level. To identify distinction-contributing protein panels for disease onset and progression, we compared the proteomic profiles of serum from healthy dogs and dogs with different stages of naturally occurring MMVD. Dogs were divided into experimental groups on the basis of the left-atrium-to-aorta ratio and normalized left ventricular internal dimension in diastole values. Serum was collected from healthy (N = 12) dogs, dogs diagnosed with MMVD in stages B1 (N = 13) and B2 (N = 12) (asymptomatic), and dogs diagnosed with MMVD in chronic stage C (N = 13) (symptomatic). Serum biochemistry and selected ELISAs (galectin-3, suppression of tumorigenicity, and asymmetric dimethylarginine) were performed. Liquid chromatography-mass spectrometry (LC-MS), tandem mass tag (TMT) quantitative proteomics, and statistical and bioinformatics analysis were employed. Most of the 21 serum proteins with significantly different abundances between experimental groups (p < 0.05, FDR ˂ 0.05) were classified as matrix metalloproteinases, protease inhibitors, scaffold/adaptor proteins, complement components, anticoagulants, cytokine, and chaperone. LC-MS TMT proteomics results obtained for haptoglobin, clusterin, and peptidase D were further validated analytically. Canine MMVD stages, including, for the first time, asymptomatic B1 and B2 stages, were successfully distinguished in dogs with the disease and healthy dogs on the basis of the relative abundances of a panel of specific serum proteins. Most proteins with significantly different abundances were involved in immune and inflammatory pathways. Their role in structural remodeling and progression of canine MMVD must be further investigated. Further research is needed to confirm the resemblance/difference with human MMVD. Proteomics data are available via ProteomeXchange with the unique dataset identifier PXD038475.

Dataset Information

Developmental basis for filamin-A-associated myxomatous mitral valve disease.

Aims

Methods and results

Conclusions

Publications

Developmental basis for filamin-A-associated myxomatous mitral valve disease.

Similar Datasets

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