Abstract
Canine myxomatous mitral valve disease (MMVD) resembles the early stages of myxomatous pathology seen in human non-syndromic mitral valve prolapse, a common valvular heart disease in the adult human population. Canine MMVD is seen in older subjects, suggesting age-related epigenetic dysregulation leading to derangements in valvular cell populations and matrix synthesis or degradation. We hypothesized that valvular interstitial cells (VICs) undergo disease-relevant changes in miRNA expression. In primary VIC lines from diseased and control valves, miRNA expression was profiled using RT-qPCR and next generation sequencing. VICs from diseased valves showed phenotypic changes consistent with myofibroblastic differentiation (vimentinlow+, α-SMAhigh+), increases in senescence markers (p21, SA-β-gαl), and decreased cell viability and proliferation potential. RT-qPCR and miRNA sequencing analyses both showed significant (p<0.05) downregulation of let-7c, miR-17, miR-20a, and miR-30d in VICs from diseased valves compared to controls. Decreased let-7c, miR-17, and miR-20a may contribute to myofibroblastic differentiation in addition to cell senescence, and decreased miR-30d may disinhibit cell apoptosis. These data support the hypothesis that epigenetic dysregulation plays an important role in age-related canine MMVD.
Highlights
Non-syndromic mitral valve prolapse (MVP) is a common valvular heart disease with a prevalence of 3% in the human adult population [1]
Most MVP events are benign, ruptured chordae or poor coaptation of the valve leaflets can lead to mitral regurgitation (MR) with ensuing congestive heart failure (CHF)
Medical management of MR is of limited value, and mitral valve repair or replacement are most effective when provided before the onset of CHF [1]
Summary
Non-syndromic mitral valve prolapse (MVP) is a common valvular heart disease with a prevalence of 3% in the human adult population [1]. Occurring myxomatous mitral valve disease (MMVD) in dogs closely resembles early stages of non-syndromic MVP in humans structurally, and functional consequences are similar, i.e., the development of cardiac enlargement and remodeling, and CHF at the end-stage of the disease. MMVD is the most common acquired cardiac disease and the most common cause of CHF in dogs, comprising 2/3 of all canine cardiac cases [2]. This disease is clearly age-related, with a lifetime prevalence in older dogs nearing 100% [2]. Once in CHF, dogs are reported to have a median survival time between 1 and 9 months [2]
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