Increased Expression of MicroRNA-206 Inhibits Potassium Voltage-Gated Channel Subfamily A Member 5 in Pulmonary Arterial Smooth Muscle Cells and Is Related to Exaggerated Pulmonary Artery Hypertension Following Intrauterine Growth Retardation in Rats
Increased Expression of MicroRNA-206 Inhibits Potassium Voltage-Gated Channel Subfamily A Member 5 in Pulmonary Arterial Smooth Muscle Cells and Is Related to Exaggerated Pulmonary Artery Hypertension Following Intrauterine Growth Retardation in Rats
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MicroRNA-206 表达增加会抑制肺动脉平滑肌细胞中钾电压门控通道亚家族 A 成员 5，并与大鼠宫内生长迟缓后肺动脉高压过度相关
DOI：
10.1161/jaha.118.010456
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发表时间：
2019-01-22
影响因子：
5.4
通讯作者：
Du, Lizhong
中科院分区：
文献类型：
--
作者：
Lv, Ying;Fu, Linchen;Du, Lizhong
背景宫内发育迟缓（IUGR）与成年肺动脉高压有关，microRNA-206（miR-206）通过转录后调节作用影响肺动脉平滑肌细胞（PASMCs）的增殖和凋亡。结果发现，慢性低氧（CH）处理后，PASMCs钾电压门控通道亚家族A成员5（Kv1.5）的表达和功能受到抑制，肺动脉高压加重。通过微阵列、聚合酶链反应和原位杂交研究了12周龄IUGR CH雄性大鼠PASMCs中microRNA的表达。在应用和不应用miR-206抑制剂的情况下，评价了来自IUGR或对照大鼠的原代培养的PASMCs和肺动脉平滑肌中Kv1.5的表达水平。还计算了右心室收缩压、细胞增殖、荧光素酶报告基因测定和/（Δ）。我们发现miR-206在12周IUGR大鼠阻力肺动脉中的表达较新生儿增加。在体内或体外应用miR-06抑制剂增加Kv1.5 α蛋白和KCNA 5的表达。此外，CH后12周龄对照组和IUGR大鼠的PASMCs中观察到右心室收缩压降低和细胞增殖，结论Kv1.5和4-aminopyridine的表达与IUGR的发生、发展密切相关，而Kv1.5和4-aminopyridine的表达与IUGR的发生、发展密切相关，Kv1.5和4-aminopyridine的表达与IUGR的发生、发展密切相关。（Kv通道特异性抑制剂）敏感性Kv电流与IUGR CH大鼠PA环和缺氧培养IUGR PASMCs中miR-206的抑制相关。因此，miR-206可能是通过Kv1.5诱导IUGR的CH肺动脉高压加重的触发因素。
Background Intrauterine growth retardation (IUGR) is related to pulmonary artery hypertension in adults, and microRNA-206 (miR-206) is proposed to affect the proliferation and apoptosis of pulmonary artery smooth muscle cells (PASMCs) via post transcriptional regulation.Methods and Results In an IUGR rat model, we found that the expression and function of potassium voltage-gated channel subfamily A member 5 (Kv1.5) in PASMCs was inhibited, and pulmonary artery hypertension was exaggerated after chronic hypoxia (CH) treatment as adults. microRNA expression was investigated in PASMCs from 12-week-old male IUGR rats with CH by microarray, polymerase chain reaction, and in situ hybridization. The expression levels of Kv1.5 in primary cultured PASMCs and pulmonary artery smooth muscle from IUGR or control rats were evaluated with and without application of an miR-206 inhibitor. Right ventricular systolic pressure, cell proliferation, luciferase reporter assay, and /(kv) wee also calculated. We found increased expression of miR-206 in resistance pulmonary arteries of IUGR rats at 12 weeks compared with newborns. Application of an miR-06 inhibitor in vivo or in vitro increased expression of Kv1.5 alpha-protein and KCNA5. Also, decreased right ventricular systolic pressure and cell proliferation were observed in PASMCs from 12-week-old control and IUGR rats after CH, while inhibitor did not significantly affect control and IUGR rats.Conclusions These results suggest that expression of Kvl.5 and 4-aminopyridine (Kv channel special inhibitor)-sensitive Kv current were correlated with the inhibition of miR-206 in PA rings of IUGR-CH rats and cultured IUGR PASMCs exposed to hypoxia. Thus, miR-206 may be a trigger for induction of exaggerated CH pulmonary artery hypertension of IUGR via Kv1.5.