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Background <p>Disturbed flow regions in the vasculature are predisposed to endothelial dysfunction and atherosclerotic plaque formation. The enzyme 12/15-lipoxygenase (12/15-LOX, encoded by ALOX15) has emerged as a promising therapeutic target for atherosclerosis. However, the relationship between 12/15-LOX and disturbed flow-induced atherosclerosis remains uncharacterized.</p> Methods <p>Expression of 12/15-LOX in endothelial cells (ECs) exposed to steady flow and disturbed flow was compared in vivo and in vitro<i>.</i> The effect of 12/15-LOX on ECs was analyzed by using ALOX15 knockout mice, EC-specific adeno-associated virus (AAV)-mediated delivery of ALOX15-shRNA, and specific inhibitors. Partial carotid ligation mouse model was established to ascertain the role of 12/15-LOX in ECs under disturbed flow.</p> Results <p>Compared to steady flow regions, 12/15-LOX was significantly upregulated in ECs at disturbed flow sites. In vivo and in vitro experiments demonstrated that 12/15-LOX promoted disturbed flow-elicited endothelial dysfunction. Mass spectrometry analysis revealed that 12/15-LOX promoted production of 15&#xa0;s-HETE, a pro-inflammatory eicosanoid metabolite, in ECs exposed to disturbed flow. Furthermore, we showed that disturbed flow activated 12/15-LOX expression through transactivation of its promoter by a mechanosensitive transcription factor sterol regulatory element binding protein 2 (SREBP2). Finally, EC-specific knockdown or inhibition of 12/15-LOX substantially attenuated the development of atherosclerosis in disturbed flow regions.</p> Conclusions <p>Disturbed flow promoted 12/15-LOX expression via SREBP2, thereby leading to increased pro-inflammatory PUFA metabolites and ECs dysfunction. Targeting at SREBP2-12/15-LOX pathway should provide therapeutic perspectives to attenuate disturbed flow-induced atherosclerosis.</p> Graphical abstract <p></p>

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12/15-lipoxygenase mediates disturbed flow-induced endothelial dysfunction and atherosclerosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月15日

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  • Jia Wei Chen,
  • Shi Li Chen,
  • Xin Rui Wu,
  • Xin Yi Shu,
  • Si Yi Tang,
  • He Yuan,
  • You Ran Li,
  • Jin Wei Quan,
  • Shuo Feng,
  • Rui Yan Zhang,
  • Chen Die Yang,
  • Lin Lu,
  • Xiao Qun Wang

摘要

Background

Disturbed flow regions in the vasculature are predisposed to endothelial dysfunction and atherosclerotic plaque formation. The enzyme 12/15-lipoxygenase (12/15-LOX, encoded by ALOX15) has emerged as a promising therapeutic target for atherosclerosis. However, the relationship between 12/15-LOX and disturbed flow-induced atherosclerosis remains uncharacterized.

Methods

Expression of 12/15-LOX in endothelial cells (ECs) exposed to steady flow and disturbed flow was compared in vivo and in vitro. The effect of 12/15-LOX on ECs was analyzed by using ALOX15 knockout mice, EC-specific adeno-associated virus (AAV)-mediated delivery of ALOX15-shRNA, and specific inhibitors. Partial carotid ligation mouse model was established to ascertain the role of 12/15-LOX in ECs under disturbed flow.

Results

Compared to steady flow regions, 12/15-LOX was significantly upregulated in ECs at disturbed flow sites. In vivo and in vitro experiments demonstrated that 12/15-LOX promoted disturbed flow-elicited endothelial dysfunction. Mass spectrometry analysis revealed that 12/15-LOX promoted production of 15 s-HETE, a pro-inflammatory eicosanoid metabolite, in ECs exposed to disturbed flow. Furthermore, we showed that disturbed flow activated 12/15-LOX expression through transactivation of its promoter by a mechanosensitive transcription factor sterol regulatory element binding protein 2 (SREBP2). Finally, EC-specific knockdown or inhibition of 12/15-LOX substantially attenuated the development of atherosclerosis in disturbed flow regions.

Conclusions

Disturbed flow promoted 12/15-LOX expression via SREBP2, thereby leading to increased pro-inflammatory PUFA metabolites and ECs dysfunction. Targeting at SREBP2-12/15-LOX pathway should provide therapeutic perspectives to attenuate disturbed flow-induced atherosclerosis.

Graphical abstract