Mechanosensitive microRNA-181b Regulates Aortic Valve Endothelial Matrix Degradation by Targeting TIMP3.
Mechanosensitive microRNA-181b Regulates Aortic Valve Endothelial Matrix Degradation by Targeting TIMP3.
复制标题
机械敏感的microRNA-181b通过靶向timp3来调节主动脉瓣内皮矩阵降解。
DOI：
10.1007/s13239-017-0296-z
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发表时间：
2018-06
影响因子：
1.8
通讯作者：
Jo H
中科院分区：
文献类型：
--
作者：
Heath JM;Fernandez Esmerats J;Khambouneheuang L;Kumar S;Simmons R;Jo H
钙化性主动脉瓣疾病（CAVD）是老年人群发病的主要原因，但其进展的潜在机制仍知之甚少。主动脉瓣钙化优先发生在纤维瘤上，纤维瘤易受扰动血流的影响。该疾病的侧特异性进展的特征在于炎症、钙化病变和细胞外基质（ECM）降解。在这里，我们探讨了机械敏感microRNA-181 b及其下游靶点在人主动脉瓣内皮细胞（HAVEC）中的作用。从机制上讲，miR-181 b在OS和纤维化中上调，其靶向TIMP 3、SIRT 1和GATA 6，与明胶酶/MMP活性增加相关。明胶酶测定显示，miR-181 b过表达导致TIMP 3降低并加剧MMP活性，miR-181 b抑制通过抑制TIMP 3水平降低明胶酶活性。荧光素酶分析显示miR-181 b与TIMP 3基因特异性结合。miR-181 b在LS或OS诱导的HAVEC中过表达可增加MMP活性，而miR-181 b抑制可消除剪切敏感性MMP活性。这些研究表明，靶向这种剪切依赖性miRNA可能为CAVD提供新的非侵入性治疗。
Calcific aortic valve disease (CAVD) is a major cause of morbidity in the aging population, but underlying mechanisms of its progression remain poorly understood. Aortic valve calcification preferentially occurs on the fibrosa, which is subjected to disturbed flow. The side-specific progression of the disease is characterized by inflammation, calcific lesions, and extracellular matrix (ECM) degradation. Here, we explored the role of mechanosensitive microRNA-181b and its downstream targets in human aortic valve endothelial cells (HAVECs). Mechanistically, miR-181b is upregulated in OS and fibrosa, and it targets TIMP3, SIRT1, and GATA6, correlated with increased gelatinase/MMP activity. Overexpression of miR-181b led to decreased TIMP3 and exacerbated MMP activity as shown by gelatinase assay, and miR-181b inhibition decreased gelatinase activity through the repression of TIMP3 levels. Luciferase assay showed specific binding of miR-181b to the TIMP3 gene. Overexpression of miR-181b in HAVECs subjected to either LS or OS increased MMP activity, and miR-181b inhibition abrogated shear-sensitive MMP activity. These studies suggest that targeting this shear-dependent miRNA may provide a novel non-invasive treatment for CAVD.
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DOI：
10.2967/jnumed.114.152355
发表时间：
2015-06
期刊：
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
影响因子：
--
作者：
Jung JJ;Razavian M;Challa AA;Nie L;Golestani R;Zhang J;Ye Y;Russell KS;Robinson SP;Heistad DD;Sadeghi MM
通讯作者：
Sadeghi MM
影响因子：
37.8
作者：
Cheung, PY;Sawicki, G;Schulz, R
通讯作者：
Schulz, R
DOI：
10.1111/j.1368-5031.2004.00219.x
发表时间：
2005-01-01
影响因子：
2.6
作者：
Hsu, SY;Hsieh, IC;Hung, KC
通讯作者：
Hung, KC
影响因子：
4.6
作者：
Rathan S;Ankeny CJ;Arjunon S;Ferdous Z;Kumar S;Fernandez Esmerats J;Heath JM;Nerem RM;Yoganathan AP;Jo H
通讯作者：
Jo H
DOI：
10.1161/atvbaha.114.303425
发表时间：
2014-10
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Kumar S;Kim CW;Simmons RD;Jo H
通讯作者：
Jo H