Division of Cardiology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
Department of Physiology and Biophysics, Graduate Institute of Physiology, National Defense Medical Center, Taipei, Taiwan.
Br J Pharmacol. 2020 Dec;177(23):5375-5392. doi: 10.1111/bph.15175. Epub 2020 Jul 20.
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.
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 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.
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.
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.
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.
脂质失调和血管炎症导致的动脉粥样硬化可引发动脉粥样硬化性心血管疾病（ASCVD），这是全球发病率和死亡率的主要原因。查耳酮及其衍生物具有多种有益特性，包括抗炎、抗氧化和抗肿瘤活性，但其心脏保护作用尚不清楚。我们旨在开发一种具有抗动脉粥样硬化潜力的有效查耳酮衍生物。
人 THP-1 细胞和 HUVEC 用作体外模型。通过 Western blot 和实时 PCR 测定蛋白、mRNA 和 miRNA 的表达。通过 H 标记胆固醇测定胆固醇流出能力。用高脂肪饮食喂养 LDL 受体敲除（Ldlr ）小鼠作为体内动脉粥样硬化模型。用苏木精和伊红及油红 O 染色分析斑块形成。
我们利用三磷酸腺苷结合盒转运体 A1（ABCA1）的表达鉴定出查耳酮衍生物 1m-6，它可增强 THP-1 巨噬细胞中 ABCA1 的表达并促进胆固醇流出。此外，1m-6 通过核因子红细胞 2 相关因子 2（Nrf2）/血红素加氧酶-1（HO-1）信号稳定 ABCA1 mRNA，并抑制潜在的 ABCA1 调节 miRNA 的表达。此外，1m-6 还可通过抑制 TNF-α诱导的黏附分子（血管细胞黏附分子 1（VCAM-1）和细胞间黏附分子 1（ICAM-1））的表达和促炎细胞因子的产生，显著抑制 JAK/STAT3 激活和 Nrf2/HO-1 信号在 HUVECs 中的调节，从而抑制 TNF-α诱导的黏附分子（血管细胞黏附分子 1（VCAM-1）和细胞间黏附分子 1（ICAM-1））的表达和促炎细胞因子的产生。在动脉粥样硬化易感小鼠中，1m-6 可显著减少脂质堆积和动脉粥样硬化斑块形成。
我们的研究表明，1m-6 通过增强胆固醇流出和抑制炎症诱导的内皮功能障碍产生了有前景的动脉粥样硬化保护作用，为治疗 ASCVD 开辟了新途径。
本文是心血管保护风险因素、合并症和合并用药专题的一部分。要查看本部分中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.23/issuetoc.
