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<p>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.</p>

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Circular RNA-Sirt1 sponges miR-27b-3p to protect vascular smooth muscle cell injury during atherosclerosis through regulating the glutamine metabolism pathway

  • 期刊论文

  • 发表日期：

    2025年6月11日

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  • Qian Song,
  • Xiang Wang,
  • Qinghua Zeng,
  • Hui Xu,
  • Lin Liu

摘要

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.