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Published on: February 25, 2016
Asperuloside as a Novel NRF2 Activator to Ameliorate Endothelial Dysfunction in High Fat Diet-Induced Obese Mice
Chufeng He1,2, Ruiwen Zhu1,2, Lei He3
1School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China.
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. Antioxid. Redox Signal. 42, 77-96.
Insights
Asperuloside (ASP) improves vascular health in obesity by activating the Nrf2/HO-1 pathway, reducing oxidative stress and endothelial dysfunction. This suggests ASP as a potential therapeutic for vascular diseases.
Area of Science:
- Biochemistry
- Pharmacology
- Cardiovascular Research
Background:
- Obesity-associated vascular diseases remain a significant clinical challenge.
- Current treatments are insufficient for endothelial dysfunction and oxidative stress.
- Asperuloside (ASP), from *Eucommia species*, has antiobesity effects but its vascular impact is unknown.
Purpose of the Study:
- To investigate the effects of Asperuloside (ASP) on vascular dysfunction in obesity.
- To elucidate the underlying mechanisms of ASP's vascular protective actions.
Main Methods:
- Obese mouse models and interleukin (IL)-1β-treated endothelial cells were used.
- Endothelium-dependent relaxations (EDRs), endothelial activation, oxidative stress, and reactive oxygen species (ROS) were assessed.
- Heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways were analyzed, including Nrf2 nuclear translocation and direct binding to the antioxidant response element (ARE).
- Cellular thermal shift assay (CETSA) was employed to confirm direct ASP-Nrf2 binding.
Main Results:
- ASP significantly improved impaired EDRs and suppressed endothelial activation in obese mice and IL-1β-treated models.
- ASP attenuated oxidative stress, scavenged mitochondrial ROS, and upregulated endothelial HO-1 expression.
- HO-1 knockdown abrogated ASP's protective effects, while endothelial cell-specific Nrf2 knockdown eliminated ASP's vascular benefits and HO-1 upregulation.
- ASP directly bound to Nrf2, facilitating its nuclear translocation and enhancing HO-1 transcription.
Conclusions:
- Asperuloside ameliorates obesity-associated endothelial dysfunction by activating the Nrf2/HO-1 signaling pathway.
- ASP maintains redox homeostasis, suggesting its potential as a novel therapeutic agent for vasculopathy.
- ASP may serve as a valuable dietary supplement for managing vascular complications.
