Long Non-coding RNA PEBP1P2 Suppresses Proliferative VSMCs Phenotypic Switching and Proliferation in Atherosclerosis
Long Non-coding RNA PEBP1P2 Suppresses Proliferative VSMCs Phenotypic Switching and Proliferation in Atherosclerosis
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长链非编码 RNA PEBP1P2 抑制动脉粥样硬化中增殖的 VSMC 表型转换和增殖
DOI：
10.1016/j.omtn.2020.08.013
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发表时间：
2020-12-04
影响因子：
8.8
通讯作者：
Xin, Hui
中科院分区：
文献类型：
--
作者：
He, Xingqiang;Lian, Zhexun;Xin, Hui
长链非编码RNA（lncRNA）在血管平滑肌细胞（VSMC）的生长中起着重要作用，其功能障碍与心血管疾病（CVD）的发生和发展密切相关。血管平滑肌细胞的异常表型转换和增殖是动脉粥样硬化发展过程中的重要事件。本研究鉴定了一种新的lncRNA，PEBP 1 P2，其作为VSMC表型转化和增殖的有价值的调节剂。在大鼠球囊损伤模型中，PEBP 1 P2在增殖的VSMC和病变动脉中的表达显著降低。此外，我们发现PEBP 1 P2在血小板衍生生长因子BB（PDGF-BB）诱导的VSMCs表型转换过程中抑制增殖、迁移和去分化。从机制上讲，细胞周期蛋白依赖性激酶9（CDK 9）被证实是PEBP 1 P2的直接靶点，PEBP 1 P2被证明介导VSMC的表型转换和增殖，并被PEBP 1 P2拯救。然后，我们探讨了临床意义，因为我们观察了PEBP 1 P2在冠心病（CHD）患者和人类颈动脉粥样硬化斑块晚期血清中的表达降低。最后，PEBP 1 P2过表达明显抑制体内新生内膜形成和VSMC表型转换。综上所述，PEBP 1 P2通过直接结合CDK 9抑制VSMC的增殖和迁移，这意味着它可能是治疗增殖性血管疾病的有希望的治疗靶点。
Long non-coding RNAs (lncRNAs) play a crucial role in the growth of vascular smooth muscle cells (VSMCs), the dysfunction of which is closely associated with the initiation and progression of cardiovascular diseases (CVDs). Abnormal phenotypic switching and proliferation of VSMCs constitute a significant event in the progression of atherosclerosis. The present study identified a novel lncRNA, PEBP1P2, which serves as a valuable regulator of VSMCs in phenotypic transformation and proliferation. The expression of PEBP1P2 was remarkably decreased in proliferating VSMCs and pathological arteries when using a balloon injury model of rats. Furthermore, we found that PEBP1P2 represses proliferation, migration, and dedifferentiation during phenotype switching in VSMCs induced by platelet-derived growth factor BB (PDGF-BB). Mechanistically, cyclin-dependent kinase 9 (CDK9) was confirmed to be the direct target of PEBP1P2, which was proven to mediate phenotypic switching and proliferation of VSMCs and was rescued by PEBP1P2. Then, we explored the clinical significance, as we observed the decreased expression of PEBP1P2 in the serum of coronary heart disease (CHD) patients and human advanced carotid atherosclerotic plaques. Finally, PEBP1P2 overexpression distinctly suppressed neointima formation and VSMC phenotypic switching in vivo. Taken together, PEBP1P2 inhibits proliferation and migration in VSMCs by directly binding to CDK9, implying that it maybe a promising therapeutic target for the treatment of proliferative vascular diseases.