Survival of activated myofibroblasts in canine myxomatous mitral valve disease and the role of apoptosis

Blake, Rachel; Markby, Greg; Culshaw, Geoff; Pereira, Yolanda Martínez; Lu, Chi-Chien; Corcoran, Brendan

doi:10.1016/j.rvsc.2019.11.004

Cited by 11 publications

(11 citation statements)

References 36 publications

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“…Activation of EndoMT has been identified in late-stage diseased canine valve, and likely then contributes to ongoing valve degeneration (Lu et al, 2015a). The association of functions of cell cycle or cell development with all grades likely relates to the proliferation and transition of VICs into activated myofibroblasts as a constant feature of disease development, and grade-dependent change in cell type, distribution and numbers has been confirmed in dogs by immuno-histochemistry (Han et al, 2008;Blake et al, 2019).…”

Section: Discussionmentioning

confidence: 93%

Disease Severity-Associated Gene Expression in Canine Myxomatous Mitral Valve Disease Is Dominated by TGFβ Signaling

et al. 2020

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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 lifetime , 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 TGFβ1, TNF, IFGN identified as the top upstream 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, TGFβ appears to be the dominant signaling pathway controlling pathogenesis irrespective of disease severity.

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Section: Discussionmentioning

confidence: 93%

Disease Severity-Associated Gene Expression in Canine Myxomatous Mitral Valve Disease Is Dominated by TGFβ Signaling

et al. 2020

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“…It must be noted that this identification was performed in cells derived from the last third of the leaflet. This specification is necessary since a wide heterogenicity of VICs was described according to the portion of the leaflet from which cells are collected (proximal or other parts) [ 28 , 29 ]. The expression of TRPV1 seemed to be stronger in canine pathological VICs compared to the physiological ones.…”

Section: Discussionmentioning

confidence: 99%

TRPV1 Receptor Identification in Bovine and Canine Mitral Valvular Interstitial Cells

Vercelli

Gambino

Amadori

et al. 2021

Veterinary Sciences

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Myxomatous mitral valve degeneration (MMVD) is the most common acquired cardiac disease in canine species, and valvular interstitial cells (VICs) are considered the main responsible for the development of this pathology. The scientific interest is focused on isolating and characterizing these cells. The aims of the present study were to verify a novel VICs mechanical isolation method and to characterize isolated cells using immunocytochemistry and immunofluorescence, with parallel histological and immunohistochemistry assays on bovine and canine healthy and MMVD mitral valves. Antibodies against vimentin (VIM), smooth muscle actin (SMA), von Willebrand (vW) factor, Transforming Growth Factor (TGF) β1, and Transient Receptor Potential Vanilloid 1 (TRPV1) were used. The isolation method was considered reliable and able to isolate only VICs. The different assays demonstrated a different expression of SMA in healthy and MMVD mitral valves, and TRPV1 was isolated for the first time from bovine and canine VICs and the correspondent mitral valve leaflets. The novelties of the present study are the new isolation method, that may allow correlations between laboratory and clinical conditions, and the identification of TRPV1, which will lead to further investigations to understand its function and possible role in the etiology of MMVD and to the design of new therapeutic strategies.

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“…Since it is not possible to obtain samples from young/healthy client-owned dogs, further investigation of other breeds susceptible to MMVD could determine if changes seen are breed-specific. We have validated, and currently are using, a robust primary VIC cell culture system for which we have transcriptomic data for cells derived from non-CKCS, and this could be used to examine further CKCS-specific differences [ 22 , 53 ]. Loss/gain of function studies for specific genes of interest could be undertaken to see if they affect the valvular cell phenotype.…”

Section: Discussionmentioning

confidence: 99%

Comparative transcriptomic profiling of myxomatous mitral valve disease in the cavalier King Charles spaniel

et al. 2020

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Background Almost all elderly dogs develop myxomatous mitral valve disease by the end of their life, but the cavalier King Charles spaniel (CKCS) has a heightened susceptibility, frequently resulting in death at a young age and suggesting that there is a genetic component to the condition in this breed. Transcriptional profiling can reveal the impact of genetic variation through differences in gene expression levels. The aim of this study was to determine whether expression patterns were different in mitral valves showing myxomatous degeneration from CKCS dogs compared to valves from non-CKCS dogs. Results Gene expression patterns in three groups of canine valves resulted in distinct separation of normal valves, diseased valves from CKCS and diseased valves from other breeds; the latter were more similar to the normal valves than were the valves from CKCS. Gene expression patterns in diseased valves from CKCS dogs were quite different from those in the valves from other dogs, both affected and normal. Patterns in all diseased valves (from CKCS and other breeds) were also somewhat different from normal non-diseased samples. Analysis of differentially expressed genes showed enrichment in GO terms relating to cardiac development and function and to calcium signalling canonical pathway in the genes down-regulated in the diseased valves from CKCS, compared to normal valves and to diseased valves from other breeds. F2 (prothrombin) (CKCS diseased valves compared to normal) and MEF2C pathway activation (CKCS diseased valves compared to non-CKCS diseased valves) had the strongest association with the gene changes. A large number of genes that were differentially expressed in the CKCS diseased valves compared with normal valves and diseased valves from other breeds were associated with cardiomyocytes including CASQ2, TNNI3 and RYR2. Conclusion Transcriptomic profiling identified gene expression changes in CKCS diseased valves that were not present in age and disease severity-matched non-CKCS valves. These genes are associated with cardiomyocytes, coagulation and extra-cellular matrix remodelling. Identification of genes that vary in the CKCS will allow exploration of genetic variation to understand the aetiology of the disease in this breed, and ultimately development of breeding strategies to eliminate this disease from the breed.

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Survival of activated myofibroblasts in canine myxomatous mitral valve disease and the role of apoptosis

Cited by 11 publications

References 36 publications

Disease Severity-Associated Gene Expression in Canine Myxomatous Mitral Valve Disease Is Dominated by TGFβ Signaling

Disease Severity-Associated Gene Expression in Canine Myxomatous Mitral Valve Disease Is Dominated by TGFβ Signaling

TRPV1 Receptor Identification in Bovine and Canine Mitral Valvular Interstitial Cells

Comparative transcriptomic profiling of myxomatous mitral valve disease in the cavalier King Charles spaniel

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