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Abstract
Aims: Current treatments are inadequate in alleviating obesity-associated vascular diseases. The development of effective therapies to ameliorate endothelial dysfunction and attenuate oxidative stress is of utmost importance. Asperuloside (ASP), a bioactive compound extracted from Eucommia species, exhibits antiobesity properties. However, the effects of ASP on vasculopathy have not been investigated. Therefore, the effects of ASP on vascular dysfunction and related mechanisms were elucidated.
Results: ASP significantly reversed the impaired endothelium-dependent relaxations (EDRs) in obese mice and interleukin (IL)-1β–treated aortas. ASP suppressed endothelial activation in obese mice aortas and IL-1β–treated endothelial cells. ASP attenuated oxidative stress, scavenged mitochondrial reactive oxygen species (ROS), and upregulated heme oxygenase-1 (HO-1) expression in endothelium, independent of its anti-inflammatory properties. HO-1 knockdown diminished the protective effects of ASP against impaired EDRs, ROS overproduction, and endothelial activation. Endothelial cell-specific nuclear factor erythroid 2–related factor 2 (Nrf2) knockdown eliminated the ASP-mediated vascular protective effects and endothelial HO-1 upregulation, emphasizing that ASP improves endothelial function by activating Nrf2/HO-1 signaling. ASP facilitated Nrf2 nuclear translocation and the direct binding of Nrf2 to antioxidant response element, thereby enhancing HO-1 transcription and scavenging ROS. The cellular thermal shift assay results provide the first experimental characterization of the direct binding of ASP to Nrf2.
Conclusions: These findings demonstrate that ASP ameliorates obesity-associated endothelial dysfunction by activating Nrf2/HO-1 signaling and thereby maintaining redox hemostasis, suggesting its potential as a novel Nrf2-targeted therapeutic agent and dietary supplement for vasculopathy.
© 2025, Mary Ann Liebert, Inc., publishers.
Results: ASP significantly reversed the impaired endothelium-dependent relaxations (EDRs) in obese mice and interleukin (IL)-1β–treated aortas. ASP suppressed endothelial activation in obese mice aortas and IL-1β–treated endothelial cells. ASP attenuated oxidative stress, scavenged mitochondrial reactive oxygen species (ROS), and upregulated heme oxygenase-1 (HO-1) expression in endothelium, independent of its anti-inflammatory properties. HO-1 knockdown diminished the protective effects of ASP against impaired EDRs, ROS overproduction, and endothelial activation. Endothelial cell-specific nuclear factor erythroid 2–related factor 2 (Nrf2) knockdown eliminated the ASP-mediated vascular protective effects and endothelial HO-1 upregulation, emphasizing that ASP improves endothelial function by activating Nrf2/HO-1 signaling. ASP facilitated Nrf2 nuclear translocation and the direct binding of Nrf2 to antioxidant response element, thereby enhancing HO-1 transcription and scavenging ROS. The cellular thermal shift assay results provide the first experimental characterization of the direct binding of ASP to Nrf2.
Conclusions: These findings demonstrate that ASP ameliorates obesity-associated endothelial dysfunction by activating Nrf2/HO-1 signaling and thereby maintaining redox hemostasis, suggesting its potential as a novel Nrf2-targeted therapeutic agent and dietary supplement for vasculopathy.
© 2025, Mary Ann Liebert, Inc., publishers.
| Original language | English |
|---|---|
| Pages (from-to) | 77-96 |
| Journal | Antioxidants & Redox Signaling |
| Volume | 42 |
| Issue number | 1-3 |
| Online published | 6 Sept 2024 |
| DOIs | |
| Publication status | Published - Jan 2025 |
Funding
This work was supported by Hong Kong Research Grants Council ( 24163117 , 14101119 , 14105022 , T12-101/23-N , 14109720 ) and National Natural Science Foundation of China ( 81970423 ).
Research Keywords
- asperuloside
- endothelial function
- HO-1
- Nrf2/ARE
- obesity
- oxidative stress
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