■内皮至间充质转化(EndMT)是一种转分化过程,其中内皮细胞(EC)采用间充质样表型。在过去的几年里,很明显,EndMT可导致多种心血管疾病.然而,EndMT发育的分子途径仍未完全了解。由于Zeste同源物2(EZH2)的表观遗传酶增强子及其伴随标记H3K27Me3已被证明在许多与EndMT相关的心血管疾病中升高,我们假设H3K27Me3是EndMT易感性的决定因素。
■为了研究H3K27Me3和EndMT之间的关联,人内皮细胞(HUVEC)中EZH2的敲低模型用于降低H3K27Me3丰度,然后使用TGFβ1诱导EndMT。分析了EndMT和纤维发生的分子标志物的表达。
■在培养的HUVECs中,H3K27Me3丰度的降低促进EndMT,但减轻纤维形成,如胶原蛋白I和III的表达降低所示。在HUVEC,H3K27Me3丰度直接影响miR29c的表达,胶原蛋白靶向miRNA。此外,在低H3K27Me3丰度的HUVEC中miR-29c的敲减部分恢复了胶原蛋白I和III的表达。期望,在血管周围纤维化大鼠中,H3K27Me3丰度增加与miR-29c表达降低相关。
■我们的数据显示内皮纤维发生是表观遗传调节途径的基础,我们证明ECs中H3K27Me3丰度的降低部分地以miR-29c依赖性方式钝化了纤维蛋白的发生。因此,减少H3K27Me3可以作为一种新的治疗策略,以减轻纤维发生,并可能被证明是有益的纤维化疾病,包括动脉粥样硬化。心脏纤维化,和PAH。
UNASSIGNED: Endothelial-to-mesenchymal transition (EndMT) is a transdifferentiation process in which endothelial cells (ECs) adopt a mesenchymal-like phenotype. Over the past few years, it became clear that EndMT can contribute to several cardiovascular pathologies. However, the molecular pathways underlying the development of EndMT remain incompletely understood. Since the epigenetic enzyme Enhancer of Zeste Homolog 2 (EZH2) and its concomitant mark H3K27Me3 have been shown to be elevated in many cardiovascular diseases that associate with EndMT, we hypothesized that H3K27Me3 is a determinant for the susceptibility of EndMT.
UNASSIGNED: To study the association between H3K27Me3 and EndMT, a knockdown model of EZH2 in human endothelial cells (HUVEC) was utilized to reduce H3K27Me3 abundance, followed by induction of EndMT using TGFβ1. The expression of molecular markers of EndMT and
fibrogenesis were analysed.
UNASSIGNED: In cultured HUVECs, a reduction of H3K27Me3 abundance facilitates EndMT but mitigates
fibrogenesis as shown by a decreased expression of collagen I and III. In HUVEC, H3K27Me3 abundance directly affects the expression of miR29c, a collagen-targeting miRNA. Additionally, knockdown of miR-29c in HUVEC with low H3K27Me3 abundance partly restored the expression of collagen I and III. Expectedly, in rats with perivascular fibrosis an increased abundance of H3K27Me3 associated with a decreased expression of miR-29c.
UNASSIGNED: our data shows that endothelial
fibrogenesis underlies an epigenetic regulatory pathway and we demonstrate that a decreased abundance of H3K27Me3 in ECs blunts
fibrogenesis in part in a miR-29c dependent manner. Therefore, a reduction of H3K27Me3 could serve as a novel therapeutical strategy to mitigate
fibrogenesis and may prove to be beneficial in fibrogenic diseases including atherosclerosis, cardiac fibrosis, and PAH.