From Vascular Biology Center (I.K., Y.W., K.P., Y.T., J.T., H.S.), Department of Biochemistry and Molecular Biology (I.K.), Medical College of Georgia (I.K., J.V.), and Department of Pharmacology and Toxicology (H.S., J.A.J.), Georgia Regents University, Augusta, GA; Center for Translational Medicine (C.J.T., W.J.K.), and Department of Pharmacology (W.J.K.), Temple University School of Medicine, Philadelphia, PA; and Department of Medicine (G.P., L.M., H.A.R.), Cell Biology (H.A.R.), and Molecular Genetics (H.A.R.), Duke University Medical Center, Durham, NC.
Circ Res. 2014 Feb 28;114(5):833-44. doi: 10.1161/CIRCRESAHA.114.302766. Epub 2013 Dec 13.
MicroRNAs (miRs) are small, noncoding RNAs that function to post-transcriptionally regulate gene expression. First transcribed as long primary miR transcripts (pri-miRs), they are enzymatically processed in the nucleus by Drosha into hairpin intermediate miRs (pre-miRs) and further processed in the cytoplasm by Dicer into mature miRs where they regulate cellular processes after activation by a variety of signals such as those stimulated by β-adrenergic receptors (βARs). Initially discovered to desensitize βAR signaling, β-arrestins are now appreciated to transduce multiple effector pathways independent of G-protein-mediated second messenger accumulation, a concept known as biased signaling. We previously showed that the β-arrestin-biased βAR agonist, carvedilol, activates cellular pathways in the heart.
Here, we tested whether carvedilol could activate β-arrestin-mediated miR maturation, thereby providing a novel potential mechanism for its cardioprotective effects.
In human cells and mouse hearts, carvedilol upregulates a subset of mature and pre-miRs, but not their pri-miRs, in β1AR-, G-protein-coupled receptor kinase 5/6-, and β-arrestin1-dependent manner. Mechanistically, β-arrestin1 regulates miR processing by forming a nuclear complex with hnRNPA1 and Drosha on pri-miRs.
Our findings indicate a novel function for β1AR-mediated β-arrestin1 signaling activated by carvedilol in miR biogenesis, which may be linked, in part, to its mechanism for cell survival.
MicroRNAs（miRs）是小的非编码 RNA，其功能是在后转录水平上调节基因表达。首先转录为长的初级 miR 转录物（pri-miRs），它们在核内经 Drosha 酶切成发夹中间 miR（pre-miRs），并在细胞质中经 Dicer 进一步加工成成熟 miR，然后在被各种信号激活后调节细胞过程，如β-肾上腺素能受体（βARs）刺激的信号。最初发现它使βAR 信号脱敏，现在β-arrestins 被认为可以独立于 G 蛋白介导的第二信使积累转导多种效应途径，这一概念称为偏向信号。我们之前表明，β-arrestin 偏向的βAR 激动剂卡维地洛激活心脏中的细胞途径。
在这里，我们测试了卡维地洛是否可以激活β-arrestin 介导的 miR 成熟，从而为其心脏保护作用提供一种新的潜在机制。
在人类细胞和小鼠心脏中，卡维地洛以上调β1AR、G 蛋白偶联受体激酶 5/6 和β-arrestin1 依赖的方式上调一组成熟和 pre-miRs，但不影响其 pri-miRs。从机制上讲，β-arrestin1 通过与 pri-miRs 上的 hnRNPA1 和 Drosha 形成核复合物来调节 miR 加工。
我们的研究结果表明，卡维地洛激活的β1AR 介导的β-arrestin1 信号在 miR 生物发生中具有新的功能，这可能部分与其细胞存活机制有关。
