Central Laboratory of Harbin Medical University (Daqing), Daqing, 163319, PR China; College of Pharmacy, Harbin Medical University, Harbin, 150081, PR China.
Central Laboratory of Harbin Medical University (Daqing), Daqing, 163319, PR China; College of Medical Laboratory Science and Technology, Harbin Medical University (Daqing), Daqing, 163319, PR China.
Eur J Pharmacol. 2024 Oct 5;980:176855. doi: 10.1016/j.ejphar.2024.176855. Epub 2024 Jul 25.
Phenotypic transformation of pulmonary artery smooth muscle cells (PASMCs) contributes to vascular remodeling in hypoxic pulmonary hypertension (PH). Recent studies have suggested that circular RNAs (circRNAs) may play important roles in the vascular remodeling of hypoxia-induced PH. However, whether circRNAs cause pulmonary vascular remodeling by regulating the phenotypic transformation in PH has not been investigated. Microarray and RT-qPCR analysis identified that circLMBR1, a novel circRNA, decreased in mouse lung tissues of the hypoxia-SU5416 PH model, as well as in human PASMCs and mouse PASMCs exposed to hypoxia. Overexpression of circLMBR1 in the Semaxinib (SU5416) mouse model ameliorated hypoxia-induced PH and vascular remodeling in the lungs. Notably, circLMBR1 was mainly distributed in the nucleus and bound to the splicing factor PUF60. CircLMBR1 suppressed the phenotypic transformation of human PASMCs and vascular remodeling by inhibiting PUF60 expression. Furthermore, we identified U2AF65 as the downstream regulatory factor of PUF60. U2AF65 directly interacted with the pre-mRNA of the contractile phenotype marker smooth muscle protein 22-α (SM22α) and inhibited its splicing. Meanwhile, hypoxia exposure increased the formation of the PUF60-U2AF65 complex, thereby inhibiting SM22α production and inducing the transition of human PASMCs from a contractile phenotype to a synthetic phenotype. Overall, our results verified the important role of circLMBR1 in the pathological process of PH. We also proposed a new circLMBR1/PUF60-U2AF65/pre-SM22α pathway that could regulate the phenotypic transformation and proliferation of human PASMCs. This study may provide new perspectives for the diagnosis and treatment of PH.
肺动脉平滑肌细胞（PASMCs）的表型转化导致低氧性肺动脉高压（PH）中的血管重塑。最近的研究表明，环状 RNA（circRNAs）可能在缺氧诱导的 PH 的血管重塑中发挥重要作用。然而，circRNAs 是否通过调节 PH 中的表型转化引起肺血管重塑尚未被研究。微阵列和 RT-qPCR 分析表明，circLMBR1，一种新的 circRNA，在缺氧-SU5416 PH 模型的小鼠肺组织中以及在暴露于缺氧的人 PASMCs 和小鼠 PASMCs 中减少。circLMBR1 在 Semaxinib（SU5416）小鼠模型中的过表达改善了缺氧诱导的 PH 和肺部的血管重塑。值得注意的是，circLMBR1 主要分布在核内并与剪接因子 PUF60 结合。circLMBR1 通过抑制 PUF60 表达抑制人 PASMCs 的表型转化和血管重塑。此外，我们鉴定出 U2AF65 是 PUF60 的下游调节因子。U2AF65 直接与收缩表型标志物平滑肌蛋白 22-α（SM22α）的前体 mRNA 相互作用并抑制其剪接。同时，缺氧暴露增加了 PUF60-U2AF65 复合物的形成，从而抑制 SM22α 的产生并诱导人 PASMCs 从收缩表型向合成表型的转变。总体而言，我们的研究结果证实了 circLMBR1 在 PH 病理过程中的重要作用。我们还提出了一个新的 circLMBR1/PUF60-U2AF65/pre-SM22α 通路，该通路可以调节人 PASMCs 的表型转化和增殖。这项研究可能为 PH 的诊断和治疗提供新的视角。
