Tang F T, Qian Z Y, Liu P Q, Zheng S G, He S Y, Bao L P, Huang H Q
Department of Pharmacology, China Pharmaceutical University, Nanjing, Jiangsu 210009, PR China.
Biochem Pharmacol. 2006 Aug 28;72(5):558-65. doi: 10.1016/j.bcp.2006.05.018. Epub 2006 Jul 31.
Our previous studies have proven that crocetin (CCT), extracted from Gardenia jasminoides Ellis, possesses the anti-atherosclerotic effect. Because endothelial dysfunction strongly contributes to the initiation and progression of atherosclerosis, the present study aims to investigate whether CCT is capable of improving this dysfunction and to explore the possible mechanisms. Endothelial dysfunction was induced by in vivo feeding high cholesterol diet (HCD) to rabbit and by in vitro treating bovine aortic endothelial cells (BAECs) with oxidized LDL (oxLDL). Endothelium-dependent relaxation (EDR) evoked by acetylcholine (Ach) and endothelium-independent relaxation (RIDR) mediated by sodium nitroprusside (SNP) of thoracic aorta isolated from rabbit were measured. The results indicated that the EDR in HCD alone treated rabbits was seriously impaired and the maximal relaxation induced by Ach (10(-5.5) M) was only 54% that in control rabbit fed with regular diet. Oral complementation with CCT (15, 30 mg/kg) dose-dependently improved this impairment and restored the maximal relaxation to 68% and 80% that in control group, respectively. However, the EIDR maintained comparable in all groups. Complementation with CCT (15, 30 mg/kg) simultaneously increased serum level of nitric oxide (NO), upregulated vessel activity and mRNA expression of endothelial NO synthase (eNOS) as well as vessel cyclic GMP (cGMP) content compared with those in rabbit treated with HCD alone. Inducible NOS (iNOS) activity remained unchangeable in all groups. In BAECs, oxLDL treatment decreased NO production, downregulated both activity and mRNA expression of eNOS. While those decrease or downregulation were inhibited by co-treatment with CCT (0.1, 1, 10 microM) in a dose-dependent manner. These findings suggested that CCT significantly restored the EDR of thoracic aorta in hypercholesterolemic rabbit, which might be explained by its action to increase the vessel eNOS activity, leading to elevation of NO production.
我们之前的研究已经证明，从栀子中提取的藏红花酸（CCT）具有抗动脉粥样硬化作用。由于内皮功能障碍在动脉粥样硬化的发生和发展中起重要作用，本研究旨在探讨CCT是否能够改善这种功能障碍，并探索其可能的机制。通过给兔子喂食高胆固醇饮食（HCD）在体内诱导内皮功能障碍，以及用氧化低密度脂蛋白（oxLDL）体外处理牛主动脉内皮细胞（BAECs）。测量从兔子分离的胸主动脉中乙酰胆碱（Ach）引起的内皮依赖性舒张（EDR）和硝普钠（SNP）介导的非内皮依赖性舒张（RIDR）。结果表明，仅用HCD处理的兔子的EDR严重受损，Ach（10^(-5.5) M）诱导的最大舒张仅为喂食正常饮食的对照兔子的54%。口服补充CCT（15、30 mg/kg）剂量依赖性地改善了这种损伤，并将最大舒张分别恢复到对照组的68%和80%。然而，EIDR在所有组中保持相当。与仅用HCD处理的兔子相比，补充CCT（15、30 mg/kg）同时增加了血清一氧化氮（NO）水平，上调了血管活性和内皮型一氧化氮合酶（eNOS）的mRNA表达以及血管环磷酸鸟苷（cGMP）含量。诱导型一氧化氮合酶（iNOS）活性在所有组中保持不变。在BAECs中，oxLDL处理降低了NO产生，下调了eNOS的活性和mRNA表达。而这些降低或下调被与CCT（0.1、1、10 microM）共同处理以剂量依赖性方式抑制。这些发现表明，CCT显著恢复了高胆固醇血症兔子胸主动脉的EDR，这可能是由于其增加血管eNOS活性的作用，导致NO产生增加所致。
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