Dataset Information

Loss of Axin2 results in impaired heart valve maturation and subsequent myxomatous valve disease.

ABSTRACT:

Aims

Myxomatous valve disease (MVD) is the most common aetiology of primary mitral regurgitation. Recent studies suggest that defects in heart valve development can lead to heart valve disease in adults. Wnt/?-catenin signalling is active during heart valve development and has been reported in human MVD. The consequences of increased Wnt/?-catenin signalling due to Axin2 deficiency in postnatal valve remodelling and pathogenesis of MVD were determined.

Methods and results

To investigate the role of Wnt/?-catenin signalling, we analysed heart valves from mice deficient in Axin2 (KO), a negative regulator of Wnt/?-catenin signalling. Axin2 KO mice display enlarged mitral and aortic valves (AoV) after birth with increased Wnt/?-catenin signalling and cell proliferation, whereas Sox9 expression and collagen deposition are decreased. At 2 months in Axin2 KO mice, the valve extracellular matrix (ECM) is stratified but distal AoV leaflets remain thickened and develop aortic insufficiency. Progressive myxomatous degeneration is apparent at 4 months with extensive ECM remodelling and focal aggrecan-rich areas, along with increased BMP signalling. Infiltration of inflammatory cells is also observed in Axin2 KO AoV prior to ECM remodelling. Overall, these features are consistent with the progression of human MVD. Finally, Axin2 expression is decreased and Wnt/?-catenin signalling is increased in myxomatous mitral valves in a murine model of Marfan syndrome, supporting the importance of Wnt/?-catenin signalling in the development of MVD.

Conclusions

Altogether, these data indicate that Axin2 limits Wnt/?-catenin signalling after birth and allows proper heart valve maturation. Moreover, dysregulation of Wnt/?-catenin signalling resulting from loss of Axin2 leads to progressive MVD.

SUBMITTER: Hulin A

PROVIDER: S-EPMC5220675 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Publications

Loss of Axin2 results in impaired heart valve maturation and subsequent myxomatous valve disease.

Hulin Alexia A Moore Vicky V James Jeanne M JM Yutzey Katherine E KE

Cardiovascular research 20161107 1

<h4>Aims</h4>Myxomatous valve disease (MVD) is the most common aetiology of primary mitral regurgitation. Recent studies suggest that defects in heart valve development can lead to heart valve disease in adults. Wnt/β-catenin signalling is active during heart valve development and has been reported in human MVD. The consequences of increased Wnt/β-catenin signalling due to Axin2 deficiency in postnatal valve remodelling and pathogenesis of MVD were determined.<h4>Methods and results</h4>To inves ...[more]

PMID: 28069701

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Project description:Myxomatous mitral valve disease (MMVD) is functionally and histologically identical to mitral valve prolapse (MVP) in humans. Currently, there are no medical treatments that can delay the progression of this valvular disease or associated cardiac remodelling. Therefore, there is a need to understand the molecular pathology associated with MMVD and MVP better, and thus identify potential therapeutic targets. Circulating exosomes contain small RNA, including miRNA, which reflect cell physiology and pathology. This study explored the association between circulating exosomal miRNA (ex-miRNA) content and MMVD, heart failure due to MMVD (MMVD-CHF) and ageing, which is strongly associated with MMVD. Ex-miRNA was isolated from old normal/healthy dogs (n = 6), young normal dogs (n = 7), dogs with MMVD (n = 7) and dogs with MMVD-CHF (n = 7). Separately, total plasma miRNA was isolated from normal dogs (n = 8), dogs with MMVD (n = 8) and dogs with MMVD-CHF (n = 11). Using reverse transcription quantitative polymerase chain reaction, exosomal miR-181c (p = 0.003) and miR-495 (p = 0.0001) significantly increased in dogs with MMVD-CHF compared to the other three groups. Exosomal miR-9 (p = 0.002) increased in dogs with MMVD and MMVD-CHF compared to age-matched (old) normal dogs. Exosomal miR-599 (p = 0.002) decreased in dogs with MMVD compared to old normal dogs. In total plasma, 58 miRNA were deemed significantly different (p < 0.04) between normal dogs, dogs with MMVD and dogs with MMVD-CHF. However, in contrast to ex-miRNA, none of the miRNA in total plasma remained statistically significant if the false discovery rate was <15%. Changes in ex-miRNA are observed in dogs as they age (miR-9, miR-495 and miR-599), develop MMVD (miR-9 and miR-599) and progress from MMVD to CHF (miR-181c and miR-495). Ex-miRNA expression-level changes appear to be more specific to disease states than total plasma miRNA. RESPONSIBLE EDITOR Elena Aikawa, Harvard Medical School, USA.

Dataset Information

Loss of Axin2 results in impaired heart valve maturation and subsequent myxomatous valve disease.

Aims

Methods and results

Conclusions

Publications

Loss of Axin2 results in impaired heart valve maturation and subsequent myxomatous valve disease.

Similar Datasets

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