Nordihydroguaiaretic acid (NDGA) inhibits ritonavir-induced endothelial dysfunction in porcine pulmonary arteries.
Nordihydroguaiaretic acid (NDGA) inhibits ritonavir-induced endothelial dysfunction in porcine pulmonary arteries.
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DOI：
10.12659/msm.882040
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发表时间：
2011-11
期刊：
影响因子：
--
通讯作者：
Chen C
中科院分区：
文献类型：
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作者：
Lü JM;Nurko J;Jiang J;Weakley SM;Lin PH;Yao Q;Chen C
HIV感染和包括HIV蛋白酶抑制剂利托那韦（RTV）在内的高活性抗逆转录病毒疗法（HAART）治疗与内皮功能障碍和包括肺动脉高压在内的心血管疾病相关。本研究的目的是确定从杂酚灌木中发现的天然草药抗氧化剂北二氢愈创木酸（NDGA）是否能保护血管组织免受rtv诱导的血管损伤。用临床相关RTV浓度（15 μmol/L）加或不加NDGA处理新鲜猪肺动脉（PA）环24小时，然后进行肌图分析血管舒张反应性。采用实时荧光定量PCR和免疫组化方法分析内皮型一氧化氮合酶（eNOS）在PA环和人肺动脉内皮细胞（HPAECs）中的表达。用荧光素增强化学发光法和谷胱甘肽法分析氧化应激水平。当缓激素浓度为10 ~ 10 mol/L时，rtv处理的PA环内皮依赖性血管松弛比对照血管减少39% (P<0.05)；与1.75和3.50 μmol/L的NDGA共培养时，松弛度分别提高25%和48%。RTV还降低了RTV处理血管的最大收缩和内皮非依赖性血管舒张，而NDGA改善了这些血管舒缩反应。此外，RTV处理显著降低了猪PAs和hpaec中eNOS mRNA水平，降低了猪PAs中eNOS的免疫反应性，而NDGA显著抑制了RTV的这一作用。此外，NDGA显著阻断rtv诱导的PA环超氧阴离子的增加，抑制rtv诱导的hpaec中谷胱甘肽的减少。NDGA可有效抑制HIV蛋白酶抑制剂RTV对猪PAs血管舒缩功能的不利影响。NDGA还能阻断rtv诱导的猪PAs和hpaec中eNOS表达的降低和氧化应激的增加。本研究可能为制定预防和治疗haart相关心血管并发症的有效策略提供有价值的信息。
HIV infection and treatment with highly active antiretroviral therapy (HAART) including HIV protease inhibitor ritonavir (RTV) have been associated with endothelial dysfunction and cardiovascular disease including pulmonary arterial hypertension. The objective of this study was to determine if nordihydroguaiaretic acid (NDGA), a natural herbal antioxidant found in the creosote bush Larrea tridentate, can protect vascular tissues against RTV-induced vascular injury. Fresh porcine pulmonary artery (PA) rings were treated with a clinically relevant concentration of RTV (15 μmol/L) with or without NDGA for 24 hours, and then subjected to myograph analysis for vasomotor reactivity. Expression of endothelial nitric oxide synthase (eNOS) in both treated PA rings and human pulmonary artery endothelial cells (HPAECs) was analyzed by real-time PCR and immunohistochemistry. Oxidative stress levels were analyzed with the lucigenin-enhanced chemiluminescence and glutathione assay. In response to bradykinin at 10−10 mol/L, RTV-treated PA rings showed a 39% reduction in endothelium-dependent vasorelaxation compared with the control vessels (P<0.05); when co-cultured with NDGA (1.75 or 3.50 μmol/L), the relaxation increased by 25% and 48%, respectively. RTV also decreased the maximal contraction and endothelium-independent vasorelaxation in RTV-treated vessels, while NDGA improved these vasomotor responses. In addition, treatment of RTV significantly decreased eNOS mRNA levels in both porcine PAs and HPAECs, and reduced eNOS immunoreactivity in porcine PAs, while NDGA significantly inhibited this effect of RTV. Furthermore, NDGA significantly blocked RTV-induced increase of superoxide anion in the PA rings and inhibited RTV-induced decrease of glutathione in HPAECs. NDGA effectively inhibits the detrimental effects of HIV protease inhibitor RTV on vasomotor functions in porcine PAs. NDGA also blocks RTV-induced decrease of eNOS expression and increase of oxidative stress in both porcine PAs and HPAECs. This study may provide valuable information for the development of effective strategies for the prevention and treatment of HAART-associated cardiovascular complications.