Circ-calm4 Serves as an miR-337-3p Sponge to Regulate Myo10 (Myosin 10) and Promote Pulmonary Artery Smooth Muscle Proliferation
Circ-calm4 Serves as an miR-337-3p Sponge to Regulate Myo10 (Myosin 10) and Promote Pulmonary Artery Smooth Muscle Proliferation
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Circ-calm4 作为 miR-337-3p 海绵调节 Myo10（肌球蛋白 10）并促进肺动脉平滑肌增殖
DOI：
10.1161/hypertensionaha.119.13715
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发表时间：
2020-03-01
期刊：
影响因子：
8.3
通讯作者：
Zhu, Daling
中科院分区：
文献类型：
--
作者：
Zhang, Junting;Li, Yiying;Zhu, Daling
肺动脉平滑肌细胞增殖是缺氧性肺动脉高压肺血管重构的病理基础。最近的研究表明，环状RNA（circRNA）可以调节包括细胞增殖在内的各种生物学过程。因此，circRNA可能在低氧性肺动脉高压肺动脉平滑肌细胞增殖中起重要作用。在本研究中，我们的目的是确定功能性circRNA，并阐明其在肺动脉高压肺动脉平滑肌细胞增殖中的作用和机制。RNA测序鉴定了67个在小鼠缺氧肺组织中差异表达的circRNA。通过生物信息学和定量聚合酶链反应的筛选揭示了来自钙调蛋白4基因的选择性剪接的circRNA（命名为circ-calm 4）的显著升高。值得注意的是，这种circRNA吸收了miR-337- 3 p。我们进一步鉴定了Myo 10（myosin 10）作为miR-337- 3 p的靶蛋白。miR-337- 3 p与Myo 10 mRNA的3 '-非翻译区结合，从而减弱Myo 10的翻译。使用功能丧失和功能获得方法，我们发现circ-calm 4通过调节细胞周期来调节细胞增殖。此外，我们验证了miR-337- 3 p和Myo 10在缺氧肺动脉平滑肌中的功能。结果提示，circ-calm 4/miR-337- 3 p/Myo 10信号转导轴在分子水平调控肺动脉平滑肌细胞增殖，为肺动脉高压的早期诊断和治疗提供了潜在的靶点。
Pulmonary artery smooth muscle cell proliferation is the pathological basis of pulmonary vascular remodeling in hypoxic pulmonary hypertension. Recent studies suggest that circular RNA (circRNA) can regulate various biological processes, including cell proliferation. Therefore, it is possible that circRNA may have important roles in pulmonary artery smooth muscle cell proliferation in hypoxic pulmonary hypertension. In the present study, we aimed to identify functional circRNAs and clarify their roles and mechanisms in pulmonary artery smooth muscle cell proliferation in pulmonary hypertension. RNA sequencing identified 67 circRNAs that were differentially expressed in hypoxic lung tissues of mice. Screening by bioinformatics and quantitative polymerase chain reaction revealed significant elevation of a circRNA derived from alternative splicing of the calmodulin 4 gene (designated circ-calm4). Notably, this circRNA absorbed miR-337-3p. We further identified Myo10 (myosin 10) as a target protein of miR-337-3p. miR-337-3p bound to the 3 '-untranslated region of Myo10 mRNA, thereby attenuating the translation of Myo10. Using loss-of-function and gain-of-function approaches, we found that circ-calm4 regulated cell proliferation by regulating the cell cycle. Additionally, we verified the functions of miR-337-3p and Myo10 in hypoxic pulmonary artery smooth muscle. Our results suggested that the circ-calm4/miR-337-3p/Myo10 signal transduction axis modulated the proliferation of pulmonary artery smooth muscle cells at the molecular level, thus establishing potential targets for the early diagnosis and treatment of pulmonary hypertension.