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Circulating exosome microRNA associated with heart failure secondary to myxomatous mitral valve disease in a
Vicky K Yang1, Kerry A Loughran1, Dawn M Meola1
1Department of Clinics Sciences, Tufts University Cummings School of Veterinary Medicine, North Grafton, USA.
Abstract:
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.
Insights
Myxomatous mitral valve disease (MMVD) in dogs shows distinct exosomal miRNA (ex-miRNA) changes with disease progression and aging. These ex-miRNA alterations are more specific to disease states than total plasma miRNA, offering potential therapeutic targets.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Biomarker Discovery
Background:
- Myxomatous mitral valve disease (MMVD) in dogs mirrors human mitral valve prolapse (MVP).
- No current medical treatments can halt MMVD progression or cardiac remodeling.
- Understanding MMVD's molecular pathology is crucial for identifying therapeutic targets.
Purpose of the Study:
- To investigate the association between circulating exosomal microRNA (ex-miRNA) profiles and MMVD, heart failure due to MMVD (MMVD-CHF), and aging in dogs.
- To determine if ex-miRNA signatures are more specific to disease states than total plasma miRNA.
- To identify potential ex-miRNA biomarkers for MMVD and its progression.
Main Methods:
- Isolation of ex-miRNA and total plasma miRNA from healthy dogs, dogs with MMVD, and dogs with MMVD-CHF.
- Quantification of miRNA levels using reverse transcription quantitative polymerase chain reaction (RT-qPCR).
- Statistical analysis to compare miRNA expression levels between groups, considering age-matching and false discovery rates.
Main Results:
- Specific ex-miRNAs (miR-181c, miR-495) significantly increased in dogs with MMVD-CHF compared to controls.
- Exosomal miR-9 increased in dogs with MMVD and MMVD-CHF versus age-matched controls.
- Exosomal miR-599 decreased in dogs with MMVD compared to age-matched controls, while total plasma miRNA changes lacked statistical significance after FDR correction.
- Ex-miRNA changes correlated with aging, MMVD development, and progression to heart failure.
Conclusions:
- Circulating exosomal miRNA profiles reflect aging, MMVD development, and progression to heart failure in dogs.
- Ex-miRNA expression levels appear more specific to disease states than total plasma miRNA.
- Identified ex-miRNAs (miR-9, miR-495, miR-599, miR-181c) represent potential biomarkers for MMVD and its complications.
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