Deletion of the microRNA-degrading nuclease, translin/trax, prevents pathogenic vascular stiffness.
Deletion of the microRNA-degrading nuclease, translin/trax, prevents pathogenic vascular stiffness.
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删除 microRNA 降解核酸酶 translin/trax 可预防致病性血管僵硬。
DOI：
10.1152/ajpheart.00153.2019
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
Das,Samarjit
中科院分区：
文献类型：
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作者：
Tuday,Eric;Nomura,Yohei;Ruhela,Deepa;Nakano,Mitsunori;Fu,Xiuping;Shah,Aparna;Roman,Barbara;Yamaguchi,Atsushi;An,StevenS;Steenbergen,Charles;Baraban,JayM;Berkowitz,DanE;Das,Samarjit
血管僵硬度在高血压的发病机制中起关键作用。最近的研究表明，血管平滑肌细胞（VSMC）中miR-181 b水平的年龄相关性降低有助于增加血管硬度。由于这些发现表明抑制miR-181 b的降解可能防止血管硬化，我们评估了microRNA降解translin/trax（TN/TX）复合物是否介导主动脉中miR-181 b的降解。因此，我们测试了TN缺失是否可以防止高血压小鼠模型中的血管硬化，该模型由慢性高盐摄入（饮用水中的4%NaCl，持续3周; HSW）诱导。通过脉搏波速度和拉伸试验监测，接受HSW应激的TN−/−小鼠未显示血管硬度增加。HSW范例中TN缺失的保护作用似乎是由其增加主动脉中miR-181 b的能力介导的，因为HSW降低了WT小鼠中miR-181 b的水平，但在TN KO小鼠中没有。我们第一次证明了干扰microRNA降解可以对血管系统产生有益的影响，并确定microRNA降解TN/TX RNase复合物作为对抗血管僵硬的潜在治疗靶点。新&值得注意的是，虽然成熟microRNA的生物起源和作用机制已经很好地理解，但对microRNA通过降解的调节知之甚少。最近的研究已经确定蛋白质复合物translin（TN）/trax（TX）是一种微RNA降解酶。在这里，我们证明了TN/TX在血管平滑肌细胞中表达。此外，TN/TX复合物的缺失选择性地增加主动脉miR-181 b，并防止由摄入高盐水引起的血管僵硬度增加。据我们所知，这是第一份描述microRNA RNAse在心血管生物学或病理学中作用的报告。
Vascular stiffness plays a key role in the pathogenesis of hypertension. Recent studies indicate that the age-associated reduction in miR-181b levels in vascular smooth muscle cells (VSMCs) contributes to increased vascular stiffness. As these findings suggest that inhibiting degradation of miR-181b might prevent vascular stiffening, we have assessed whether the microRNA-degrading translin/trax (TN/TX) complex mediates degradation of miR-181b in the aorta.We found that TN−/−mice display elevated levels of miR-181b expression in the aorta. Therefore, we tested whether TN deletion prevents vascular stiffening in a mouse model of hypertension, induced by chronic high-salt intake (4%NaCl in drinking water for 3 wk; HSW). TN−/−mice subjected to HSW stress do not show increased vascular stiffness, as monitored by pulse wave velocity and tensile testing. The protective effect of TN deletion in the HSW paradigm appears to be mediated by its ability to increase miR-181b in the aorta since HSW decreases levels of miR-181b in WT mice, but not in TN KO mice. We demonstrate for the first time that interfering with microRNA degradation can have a beneficial impact on the vascular system and identify the microRNA-degrading TN/TX RNase complex as a potential therapeutic target in combatting vascular stiffness.NEW & NOTEWORTHYWhile the biogenesis and mechanism of action of mature microRNA are well understood, much less is known about the regulation of microRNA via degradation. Recent studies have identified the protein complex, translin(TN)/trax(TX), as a microRNA-degrading enzyme. Here, we demonstrate that TN/TX is expressed in vascular smooth muscle cells. Additionally, deletion of the TN/TX complex selectively increases aortic miR-181b and prevents increased vascular stiffness caused by ingestion of high-salt water. To our knowledge, this is first report describing the role of a microRNA RNAse in cardiovascular biology or pathobiology.