Song Qian, Wang Xiang, Zeng Qinghua, Xu Hui, Liu Lin
Department of Osteo-Internal Medicine, Tianjin Hospital, Tianjin University, Tianjin, China.
General Practice Center, Sichuan Academy of Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology, Chengdu, 610072 China.
Cytotechnology. 2025 Aug;77(4):122. doi: 10.1007/s10616-025-00759-x. Epub 2025 Jun 11.
Atherosclerosis is a progressive pathological disorder resulting in various vital cardiovascular diseases such as myocardial infarction and stroke, leading to high mortality worldwide. Currently, the precise mechanisms of pathogenesis and progression of atherosclerosis remained unclear. Circular RNAs (circRNAs) have been implicated in vital processes of cardiovascular disease. In this study, we aimed to investigate the roles of circSirt1 in vascular smooth muscle cell (VSMC) injury during atherosclerosis. We found circSirt1 was significantly downregulated in VSMCs from atherosclerosis patients compared with those from healthy controls. Under oxidative stress, expression of circSirt1 was remarkedly suppressed in VSMCs. Notably, overexpression of circSirt1 effectively protected the oxidative stress-induced VSMC injury. On the other way, miRNA-27b-3p was high-expressed in VSMCs from atherosclerosis patients and was effectively induced under oxidative stress. Overexpression of miR-27b-3p exacerbated the oxidative stress-induced VSMC injury. From the non-coding RNA service, starBase, circSirt1 was predicted to interact with miR-27b-3p. This association was further validated by RNA pull-down and luciferase assays. We detected glutamine metabolism rate was depressed under oxidative stress and low glutamine supply rendered VSMCs more susceptible to oxidative stress. Furthermore, we identified the glutamine metabolism key enzyme, glutaminase (GLS) as a direct target of miR-27b-3p in VSMCs. miR-27b-3p blocked glutamine metabolism and promoted VSMC cell injury through direct targeting GLS. Finally, rescue experiments verified the circSirt1-protected VSMC injury was through regulating the miR-27b-3p-GLS axis that restoration of miR-27b-3p in circSirt1-overexpressed VSMCs successfully overrode the high-circSirt1-moduated miR-27b-3p and GLS expressions and the oxidative stress-induced VSMC injury. Summarily, these results unveiled vital roles and molecular mechanisms of circSirt1 in oxidative stress-induced VSMC injury during atherosclerosis by regulating the miR-27b-3p-GLS axis, indicating rescue of circSirt1 in VSMCs could be an effectively therapeutic approach to treat atherosclerosis.
The online version contains supplementary material available at 10.1007/s10616-025-00759-x.
动脉粥样硬化是一种进行性病理疾病，可导致各种重要的心血管疾病，如心肌梗死和中风，在全球范围内导致高死亡率。目前，动脉粥样硬化发病机制和进展的确切机制仍不清楚。环状RNA（circRNAs）已被证明参与心血管疾病的重要过程。在本研究中，我们旨在探讨circSirt1在动脉粥样硬化过程中血管平滑肌细胞（VSMC）损伤中的作用。我们发现，与健康对照者相比，动脉粥样硬化患者VSMC中circSirt1显著下调。在氧化应激下，VSMC中circSirt1的表达明显受到抑制。值得注意的是，circSirt1的过表达有效地保护了氧化应激诱导的VSMC损伤。另一方面，miRNA-27b-3p在动脉粥样硬化患者的VSMC中高表达，并在氧化应激下有效诱导。miR-27b-3p的过表达加剧了氧化应激诱导的VSMC损伤。通过非编码RNA服务starBase预测circSirt1与miR-27b-3p相互作用。RNA下拉和荧光素酶测定进一步验证了这种关联。我们检测到氧化应激下谷氨酰胺代谢率降低，低谷氨酰胺供应使VSMC对氧化应激更敏感。此外，我们确定谷氨酰胺代谢关键酶谷氨酰胺酶（GLS）是VSMC中miR-27b-3p的直接靶点。miR-27b-3p通过直接靶向GLS阻断谷氨酰胺代谢并促进VSMC细胞损伤。最后，拯救实验证实circSirt1保护VSMC损伤是通过调节miR-27b-3p-GLS轴，即circSirt1过表达的VSMC中miR-27b-3p的恢复成功抵消了高circSirt1调节的miR-27b-3p和GLS表达以及氧化应激诱导的VSMC损伤。总之，这些结果揭示了circSirt1在动脉粥样硬化过程中通过调节miR-27b-3p-GLS轴在氧化应激诱导的VSMC损伤中的重要作用和分子机制，表明拯救VSMC中的circSirt1可能是治疗动脉粥样硬化的有效治疗方法。
在线版本包含可在10.1007/s10616-025-00759-x获取的补充材料。
