MicroRNA Profiles in Calcified and Healthy Aorta Differ: Therapeutic Impact of miR-145 and miR-378.
MicroRNA Profiles in Calcified and Healthy Aorta Differ: Therapeutic Impact of miR-145 and miR-378.
复制标题
钙化主动脉和健康主动脉中的 MicroRNA 谱存在差异：miR-145 和 miR-378 的治疗影响。
DOI：
10.1152/physiolgenomics.00074.2020
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发表时间：
2020
影响因子：
4.6
通讯作者：
Rogers,MelissaB
中科院分区：
文献类型：
--
作者：
Tang,Ying;Shah,TapanA;Yurkow,EdwardJ;Rogers,MelissaB
我们的目标是阐明在Klothomouse肾病模型中病理性钙化过程中观察到的可能抑制过量骨形态发生蛋白（BMP）信号传导的microRNAs（miRNAs）。我们假设，恢复正常水平的转录后抑制成骨钙化因子的miRNA可能会减少主动脉钙化。我们在健康主动脉中的miRNAs相对丰度谱与钙化小鼠主动脉中的miRNAs相对丰度谱有很大不同。这些miRNAs中的许多被预测为调节参与BMP信号传导的蛋白质，并且可能控制骨生成。根据三个标准选择了两种差异调节的miRNA，miR-145和miR-378：钙化主动脉中水平降低，在BMP信号通路中靶向一种以上蛋白质的能力，以及人类和小鼠之间靶向序列的保守性。在Klothomice肾功能不全患者中，使用慢病毒载体强制表达表明，恢复正常水平可抑制BMP 2和其他促成骨蛋白的合成，并抑制病理性主动脉钙化。这项研究鉴定了可能影响两性BMP信号传导的miRNA，并证明了所选miRNA在体内减少主动脉钙化的功效。骨生成异常导致的主动脉和主动脉瓣钙化在肾病、糖尿病和高胆固醇患者中很常见。这种血管成骨是临床上显著的特征。本文所述的钙化调节miRNA是慢性肾脏疾病和其他前钙化性疾病背景下的生物标志物和“miRNA替代疗法”的候选者。
Our goal was to elucidate microRNAs (miRNAs) that may repress the excess bone morphogenetic protein (BMP) signaling observed during pathological calcification in theKlothomouse model of kidney disease. We hypothesized that restoring healthy levels of miRNAs that posttranscriptionally repress osteogenic calcific factors may decrease aortic calcification. Our relative abundance profiles of miRNAs in healthy aorta differ greatly from those in calcified mouse aorta. Many of these miRNAs are predicted to regulate proteins involved in BMP signaling and may control osteogenesis. Two differentially regulated miRNAs, miR-145 and miR-378, were selected based on three criteria: reduced levels in calcified aorta, the ability to target more than one protein in the BMP signaling pathway, and conservation of targeted sequences between humans and mice. Forced expression using a lentiviral vector demonstrated that restoring normal levels repressed the synthesis of BMP2 and other pro-osteogenic proteins and inhibited pathological aortic calcification inKlothomice with renal insufficiency. This study identified miRNAs that may impact BMP signaling in both sexes and demonstrated the efficacy of selected miRNAs in reducing aortic calcification in vivo. Calcification of the aorta and the aortic valve resulting from abnormal osteogenesis is common in those with kidney disease, diabetes, and high cholesterol. Such vascular osteogenesis is a clinically significant feature. The calcification modulating miRNAs described here are candidates for biomarkers and “miRNA replacement therapies” in the context of chronic kidney disease and other procalcific conditions.