AK098656, a Novel Vascular Smooth Muscle Cell-Dominant Long Noncoding RNA, Promotes Hypertension
AK098656, a Novel Vascular Smooth Muscle Cell-Dominant Long Noncoding RNA, Promotes Hypertension
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AK098656，一种新型血管平滑肌细胞主导的长非编码 RNA，可促进高血压
DOI：
10.1161/hypertensionaha.117.09651
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发表时间：
2018-02-01
期刊：
影响因子：
8.3
通讯作者：
Cai, Jun
中科院分区：
文献类型：
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作者：
Jin, Ling;Lin, Xianjuan;Cai, Jun
最近的研究报道了一些长非编码RNA（lncRNA）介导的血管平滑肌细胞（VSMC）表型转换，这是血管疾病的常见病理生理过程。然而，人类特异性表达的lncRNA是否会调节VSMC表型并参与原发性高血压的发病机制仍不清楚。通过比较高血压患者和健康对照之间的循环lncRNA表达谱，我们鉴定了lncRNA-AK098656，该lncRNA-AK098656在高血压患者血浆中强烈上调，并且主要在VSMC中表达。 AK098656 通过增加 VSMC 增殖和迁移、升高细胞外基质蛋白、同时降低收缩蛋白来促进 VSMC 合成表型。此外，AK098656 被证明可直接与 VSMC 特异性收缩蛋白肌球蛋白重链 11 和细胞外基质的重要成分纤连蛋白 1 结合，并最终通过蛋白降解降低这些蛋白水平。 AK098656 还被证明可以与 26S 蛋白酶体非 ATP 酶调节亚基 11 结合，并促进肌球蛋白重链 11 与该蛋白质相互作用。在体内，AK098656 转基因大鼠表现出自发性高血压，具有升高的 VSMC 合成表型和狭窄的阻力动脉。转基因大鼠还表现出轻微的心脏肥厚，没有其他并发症，这与高血压的早期病理生理变化相似。所有这些数据表明AK098656是一种新的人类VSMC主导的lncRNA，它可以通过加速收缩蛋白降解、增加VSMC合成表型并最终缩小阻力动脉来促进高血压。
Recent studies reported some long noncoding RNAs (lncRNAs)-mediated vascular smooth muscle cells (VSMCs) phenotypic switch, which was a common pathophysiological process of vascular diseases. However, whether human-specific expressed lncRNAs would modulate VSMCs phenotype and participate into the pathogenesis of essential hypertension remains unclear. By comparing the circulating lncRNAs expression profiles between hypertensive patients and healthy controls, we identified a lncRNA-AK098656, strongly upregulated in the plasma of hypertensive patients, and predominantly expressed in VSMCs. AK098656 promoted VSMCs synthetic phenotype evidenced by increasing VSMC proliferation and migration, elevating extracellular matrix proteins, whereas lowering contractile proteins. Furthermore, AK098656 was demonstrated to directly bind with the VSMCs-specific contractile protein, myosin heavy chain-11, and an essential component of extracellular matrix, fibronectin-1, and finally lowered these protein levels through protein degradation. AK098656 was also shown to bind with 26S proteasome non-ATPase regulatory subunit 11 and facilitated myosin heavy chain-11 to interact with this protein. In vivo, AK098656 transgenic rats showed spontaneous development of hypertension, with elevated VSMCs synthetic phenotype and narrowed resistant arteries. Transgenic rats also showed slight cardiac hypertrophy without other complications, which was similar with early pathophysiological changes of hypertension. All these data indicated AK098656 as a new human VSMC-dominant lncRNA, which could promote hypertension through accelerating contractile protein degradation, increasing VSMC synthetic phenotype, and finally narrowed resistance arteries.