Short‐term intensive atorvastatin therapy improves endothelial function partly via attenuating perivascular adipose tissue inflammation through 5‐lipoxygenase pathway in hyperlipidemic rabbits
Short‐term intensive atorvastatin therapy improves endothelial function partly via attenuating perivascular adipose tissue inflammation through 5‐lipoxygenase pathway in hyperlipidemic rabbits
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DOI：
10.3760/cma.j.issn.0366-6999.20133011
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发表时间：
2014-08
影响因子：
6.1
通讯作者：
Xiaoqiao Wang;Yongqing Lin;N. Luo;Zhongqing Chen;Miao-ning Gu;Jingfeng Wang;Yangxin Chen
中科院分区：
文献类型：
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作者：
Xiaoqiao Wang;Yongqing Lin;N. Luo;Zhongqing Chen;Miao-ning Gu;Jingfeng Wang;Yangxin Chen
动脉粥样硬化是一种具有多种危险因素的疾病，其中高脂血症是导致其发病和发展的主要经典危险因素。本研究的目的是确定短期强化阿托伐他汀（IA）治疗对血管内皮功能的影响，并探讨可能有助于解释短期强化他汀治疗的临床益处的可能机制。方法在高脂饮食（HFD） 8周后，分别给予IA或低剂量阿托伐他汀（LA）治疗5天。分别测量血脂、C反应蛋白（CRP）、肿瘤坏死因子（TNF）、白细胞介素- 6 （IL - 6）、一氧化氮（NO）、内皮素- 1 （ET - 1）和内皮依赖性血管舒张功能。在颈动脉周围脂肪组织（PCAT）和培养的脂肪细胞中，我们还评估了CRP、TNF‐、IL‐6、巨噬细胞趋化蛋白‐1 （MCP‐1）和5‐脂氧合酶（5‐LO）的mRNA和蛋白表达。结果HFD可提高血清炎症因子水平；诱发明显的高脂血症和内皮功能障碍，包括NO和ET‐1之间的失衡；炎症因子和5‐LO表达增强；促进巨噬细胞向脂肪组织浸润。5天的IA治疗可显著降低血清炎症因子水平及其在PCAT中的表达；恢复NO和ET‐1之间的平衡；改善内皮功能和巨噬细胞浸润，血脂无明显变化。然而，在LA治疗中没有观察到上述所有情况。体外实验发现，脂多糖（LPS）可增强炎性因子和5‐LO在体外培养脂肪细胞中的表达，高剂量（5 mol/L）阿托伐他汀短时间（6小时）处理可减弱炎症因子和5‐LO的表达，但低剂量（0.5 mol/L）阿托伐他汀不能减弱炎症因子和5‐LO的表达。此外，肉桂酰- 3,4 -二羟基-氰肉桂酸酯（CDC，一种有效的直接5‐LO抑制剂）抑制5‐LO可以显著下调LPS处理的脂肪细胞中上述基因的表达。结论短期IA治疗可显著改善HFD诱导的内皮功能障碍，其部分原因可能是通过抑制5 - LO通路减轻PCAT的炎症。
Background Atherosclerosis is a kind of disease with multiple risk factors, of which hyperlipidemia is a major classical risk factor resulting in its pathogenesis and development. The aim of this study was to determine the effects of short‐term intensive atorvastatin (IA) therapy on vascular endothelial function and explore the possible mechanisms that may help to explain the clinical benefits from short‐term intensive statin therapy. Methods After exposure to high‐fat diet (HFD) for 8 weeks, the animals were, respectively, treated with IA or low‐dose atorvastatin (LA) for 5 days. Blood lipids, C‐reactive protein (CRP), tumor necrosis factor‐ (TNF‐), interleukin‐6 (IL‐6), nitric oxide (NO), endothelin‐1 (ET‐1), and endothelium‐dependent vasorelaxation function were, respectively, measured. mRNA and protein expression of CRP, TNF‐, IL‐6, macrophage chemoattractant protein‐1 (MCP‐1), and 5‐lipoxygenase (5‐LO) were also evaluated in pericarotid adipose tissue (PCAT) and cultured adipocytes. Results HFD increased serum inflammatory factor levels; induced significant hyperlipidemia and endothelial dysfunction, including imbalance between NO and ET‐1; enhanced inflammatory factors and 5‐LO expression; and promoted macrophage infiltration into adipose tissue. Five‐day IA therapy could significantly decrease serum inflammatory factor levels and their expression in PCAT; restore the balance between NO and ET‐1; and improve endothelial function and macrophage infiltration without significant changes in blood lipids. However, all of the above were not observed in LA therapy. In vitro experiment found that lipopolysaccharide (LPS) enhanced the expression of inflammatory factors and 5‐LO in cultured adipocytes, which could be attenuated by short‐time (6 hours) treatment of high‐dose (5 mol/L) but not low‐dose (0.5 mol/L) atorvastatin. In addition, inhibiting 5‐LO by Cinnamyl‐3,4‐dihydroxy‐‐cyanocinnamate (CDC, a potent and direct 5‐LO inhibitor) could significantly downregulate the above‐mentioned gene expression in LPS‐treated adipocytes. Conclusion Short‐term IA therapy could significantly ameliorate endothelial dysfunction induced by HFD, which may be partly due to attenuating inflammation of PCAT through inhibiting 5‐LO pathway.