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<p>Atherosclerosis serves as the main pathological basis of numerous cardiovascular diseases and begins with endothelial cell activation. The traditional Chinese medicine <i>Rhizoma Corydalis</i> has garnered significant attention for its efficacy in treating cardiovascular conditions. However, its specific molecular mechanism remains unclear. This research sought to systematically explore the effects of levo-corydalmine (<i>l</i>-CDL) on endothelial proinflammatory activation and the related mechanisms. Network pharmacology combined with molecular docking assays was employed to construct a compound-target-pathway network and determine the optimal binding affinities between the compounds and atherosclerosis-related targets. Additionally, experimental studies were conducted to validate the regulatory effects of <i>l</i>-CDL on endothelial proinflammatory activation and vascular tension. Network pharmacology and molecular docking analysis revealed that <i>l</i>-CDL exhibited strong binding affinities for several core atherosclerosis-related targets. The results of the CCK-8, qRT-PCR, western blot, SA-β-gal staining, and fluorescence assays revealed that <i>l</i>-CDL suppressed ox-LDL-induced endothelial cell activation by increasing cell viability, alleviating inflammatory and senescence marker levels, and upregulating endothelial nitric oxide synthase (eNOS) in endothelial cells. A vascular ring assay further demonstrated that <i>l</i>-CDL promoted endothelium-dependent vasodilation under both physiological and ox-LDL-induced pathological conditions. Mechanistically, RNA sequencing and luciferase reporter gene analyses revealed that <i>l</i>-CDL inhibited the transcriptional activity of DNA damage inducible transcript 3 (DDIT3) and subsequently promoted eNOS expression, and these effects can be reversed by overexpression of DDIT3. This study revealed that <i>l</i>-CDL enhances eNOS expression by inhibiting DDIT3 expression, thereby suppressing ox-LDL-induced endothelial cell activation and improving vasodilatation. These findings indicate that <i>l</i>-CDL could be a potential therapeutic agent for preventing and treating endothelial proinflammatory activation and atherosclerosis.</p> Graphical Abstract <p></p>

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Levo-corydalmine derived from Rhizoma Corydalis suppresses Ox-LDL-induced endothelial cell activation and improves vasodilatation by regulating the DDIT3-eNOS pathway

  • 期刊论文

  • 发表日期：

    2025年4月7日

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  • Shaoxia Xie,
  • Jiajie Chen,
  • Zhuoming Li,
  • Wenwei Luo,
  • Shilong Zhong,
  • Weihua Lai

摘要

Atherosclerosis serves as the main pathological basis of numerous cardiovascular diseases and begins with endothelial cell activation. The traditional Chinese medicine Rhizoma Corydalis has garnered significant attention for its efficacy in treating cardiovascular conditions. However, its specific molecular mechanism remains unclear. This research sought to systematically explore the effects of levo-corydalmine (l-CDL) on endothelial proinflammatory activation and the related mechanisms. Network pharmacology combined with molecular docking assays was employed to construct a compound-target-pathway network and determine the optimal binding affinities between the compounds and atherosclerosis-related targets. Additionally, experimental studies were conducted to validate the regulatory effects of l-CDL on endothelial proinflammatory activation and vascular tension. Network pharmacology and molecular docking analysis revealed that l-CDL exhibited strong binding affinities for several core atherosclerosis-related targets. The results of the CCK-8, qRT-PCR, western blot, SA-β-gal staining, and fluorescence assays revealed that l-CDL suppressed ox-LDL-induced endothelial cell activation by increasing cell viability, alleviating inflammatory and senescence marker levels, and upregulating endothelial nitric oxide synthase (eNOS) in endothelial cells. A vascular ring assay further demonstrated that l-CDL promoted endothelium-dependent vasodilation under both physiological and ox-LDL-induced pathological conditions. Mechanistically, RNA sequencing and luciferase reporter gene analyses revealed that l-CDL inhibited the transcriptional activity of DNA damage inducible transcript 3 (DDIT3) and subsequently promoted eNOS expression, and these effects can be reversed by overexpression of DDIT3. This study revealed that l-CDL enhances eNOS expression by inhibiting DDIT3 expression, thereby suppressing ox-LDL-induced endothelial cell activation and improving vasodilatation. These findings indicate that l-CDL could be a potential therapeutic agent for preventing and treating endothelial proinflammatory activation and atherosclerosis.

Graphical Abstract