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A chalcone derivative, 1m-6, exhibits atheroprotective effects by increasing cholesterol efflux and reducing
Liv Weichien Chen1, Min-Chien Tsai2, Ching-Yuh Chern3
1Division of Cardiology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
Insights
A novel chalcone derivative, 1m-6, effectively reduces cholesterol buildup and inflammation in blood vessels. This compound shows significant potential for preventing atherosclerotic cardiovascular disease (ASCVD) by promoting cholesterol efflux and inhibiting endothelial dysfunction.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Molecular Biology
Background:
- Atherosclerotic cardiovascular disease (ASCVD) is a major global health burden driven by lipid dysregulation and vascular inflammation.
- Chalcone derivatives are known for anti-inflammatory and antioxidant properties, but their cardioprotective effects remain largely unexplored.
- There is a need for novel therapeutic agents to combat ASCVD.
Purpose of the Study:
- To develop and evaluate an effective chalcone derivative with antiatherogenic potential.
- To investigate the molecular mechanisms underlying the atheroprotective effects of the identified chalcone derivative.
- To assess the efficacy of the chalcone derivative in preclinical models of atherosclerosis.
Main Methods:
- In vitro studies using THP-1 macrophages and human umbilical vein endothelial cells (HUVECs).
- Western blot and real-time PCR for gene and protein expression analysis.
- In vivo studies using LDL receptor knockout mice fed a high-fat diet to model atherosclerosis.
Main Results:
- The chalcone derivative 1m-6 enhances ATP-binding cassette transporter A1 (ABCA1) expression and promotes cholesterol efflux in macrophages.
- 1m-6 stabilizes ABCA1 mRNA, suppresses atherogenic miRNAs, and inhibits TNF-α-induced endothelial inflammation via Nrf2/HO-1 and JAK/STAT3 pathways.
- In vivo, 1m-6 significantly reduces lipid accumulation and atherosclerotic plaque formation in mice.
Conclusions:
- The chalcone derivative 1m-6 exhibits significant atheroprotective effects.
- 1m-6 enhances cholesterol efflux and suppresses endothelial dysfunction, offering a potential new therapeutic strategy for ASCVD.
- Further research into 1m-6 could lead to novel treatments for atherosclerotic cardiovascular disease.
Background And Purpose:
Atherosclerosis, resulting from lipid dysregulation and vascular inflammation, causes atherosclerotic cardiovascular disease (ASCVD), which contributes to morbidity and mortality worldwide. Chalcone and its derivatives possess beneficial properties, including anti-inflammatory, antioxidant and antitumour activity with unknown cardioprotective effects. We aimed to develop an effective chalcone derivative with antiatherogenic potential.
Experimental Approach:
Human THP-1 cells and HUVECs were used as in vitro models. Western blots and real-time PCRs were performed to quantify protein, mRNA and miRNA expressions. The cholesterol efflux capacity was assayed by 3 H labelling of cholesterol. LDL receptor knockout (Ldlr-/- ) mice fed a high-fat diet were used as an in vivo atherogenesis model. Haematoxylin and eosin and oil red O staining were used to analyse plaque formation.
Key Results:
Using ATP-binding cassette transporter A1 (ABCA1) expression we identified the chalcone derivative, 1m-6, which enhances ABCA1 expression and promotes cholesterol efflux in THP-1 macrophages. Moreover, 1m-6 stabilizes ABCA1 mRNA and suppresses the expression of potential ABCA1-regulating miRNAs through nuclear factor erythroid 2-related factor 2 (Nrf2)/haem oxygenase-1 (HO-1) signalling. Additionally, 1m-6 significantly inhibits TNF-α-induced expression of adhesion molecules, vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1), plus production of proinflammatory cytokines via inhibition of JAK/STAT3 activation and the modulation of Nrf2/HO-1 signalling in HUVECs. In atherosclerosis-prone mice, 1m-6 significantly reduces lipid accumulation and atherosclerotic plaque formation.
Conclusion And Implications:
Our study demonstrates that 1m-6 produces promising atheroprotective effects by enhancing cholesterol efflux and suppressing inflammation-induced endothelial dysfunction, which opens a new avenue for treating ASCVD.
Linked Articles:
This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.23/issuetoc.
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