miPEP31 inhibits the vascular smooth muscle cell proliferation via cooperation with transcription factor Trps1

Our previous study has found that miPEP31, which is encoded by pri-miRNA-31, inhibits the transcription of pri-miRNA-31 and alleviates angiotensin (Ang) II-induced hypertension. miR-31 is involved in proliferation of primary vascular smooth muscle cells (VSMCs), the key functional cells involved in hypertensive vascular remodeling. However, the role and mechanism of miPEP31 in the proliferation of VSMCs remain unclear. The aim of this study is to investigate whether miPEP31 plays an important role in VSMC proliferation and contributes to vascular remodeling. We found that the administration of synthetic miPEP31 mitigated but miPEP31 deficiency aggravated the Ang II-induced aortic thickness of intima plus media and fibrotic area. miPEP31 is endogenously expressed and penetrates into nuclei in VSMCs. miPEP31 inhibits PDGF-BB-induced VSMC proliferation in a dose-dependent manner and decreases the Ang Ⅱ-induced aortic α-SMA staining area. Mechanistically, we demonstrated that miPEP31 acts as a transcriptional repressor and inhibits miR-31 expression by cooperating with Trps1, a GATA family zinc finger transcription factor. In summary, our study suggests that miPEP31 protects against vascular remodeling in Ang II-infused mice via cooperation with transcription factor Trps1 to inhibit miR-31 expression and, subsequently, VSMC proliferation. This finding highlights the therapeutic effect and role of miPEP31 on hypertensive target organs and functional cells.

我们前期研究发现，由pri-miRNA-31编码的miPEP31可抑制pri-miRNA-31的转录，并缓解血管紧张素（Ang）Ⅱ诱导的高血压。miR-31参与原代血管平滑肌细胞（VSMCs）的增殖，而VSMCs是高血压血管重构的关键功能细胞。然而，miPEP31在VSMCs增殖中的作用及机制仍不明确。本研究旨在探讨miPEP31是否在VSMCs增殖中发挥重要作用，并参与血管重构过程。我们观察到，外源性给予合成的miPEP31可减轻Ang Ⅱ诱导的小鼠主动脉内膜-中膜增厚及纤维化面积，而miPEP31缺失则会加重上述病变。miPEP31在VSMCs中呈内源性表达，并可定位于细胞核。miPEP31以剂量依赖性方式抑制血小板衍生生长因子-BB（PDGF-BB）诱导的VSMCs增殖，同时可减少Ang Ⅱ诱导的主动脉α平滑肌肌动蛋白（α-SMA）阳性染色区域。机制研究显示，miPEP31作为转录抑制因子，可通过与GATA家族锌指转录因子Trps1协同作用，抑制miR-31的表达。综上，本研究表明，miPEP31可通过与转录因子Trps1协同抑制miR-31的表达，进而抑制VSMCs增殖，从而减轻Ang Ⅱ输注小鼠的血管重构。该研究结果阐明了miPEP31在高血压靶器官及功能细胞中的治疗潜力与作用价值。