Dysregulation of valvular interstitial cell let-7c, miR-17, miR-20a, and miR-30d in naturally occurring canine myxomatous mitral valve disease

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+, a-SMAhigh+), increases in senescence markers (p21, SA-b-gal), and decreased cell viability and proliferation potential. RT-qPCR and miRNA sequencing analyses both showed significant (p&lt;0.05) downregulation of let-7c, miR-17, miR-20a, and miR-30d in ...犬黏液样变性二尖瓣疾病（MMVD）与人类非综合征性二尖瓣脱垂的黏液样病理早期阶段表现相似，后者是成人人群中常见的瓣膜性心脏病。犬MMVD多见于老年个体，提示年龄相关的表观遗传失调会引发瓣膜细胞群异常以及基质合成或降解紊乱。我们提出假说：瓣膜间质细胞（VICs）会出现与疾病相关的微小RNA（miRNA）表达变化。在取自病变瓣膜与对照瓣膜的原代VIC系中，研究人员通过实时定量聚合酶链反应（RT-qPCR）与下一代测序对miRNA表达谱进行了分析。病变瓣膜来源的VICs呈现出与肌成纤维细胞分化一致的表型改变（波形蛋白低表达阳性、α-平滑肌肌动蛋白高表达阳性），衰老标志物（p21、SA-β-gal）表达上调，同时细胞活力与增殖潜能下降。实时定量聚合酶链反应与miRNA测序分析均显示，let-7c、miR-17、miR-20a及miR-30d的表达显著下调（p<0.05）……