title: Short-term intensive atorvastatin therapy improves endothelial function partly via attenuating perivascular adipose tissue inflammation through 5-lipoxygenase pathway in hyperlipidemic rabbits.
abstract: 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-α (TNF-α), 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-α, 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 µmol/L) but not low-dose (0.5 µmol/L) atorvastatin. In addition, inhibiting 5-LO by Cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC, a potent and direct 5-LO inhibitor) could significantly downregulate the above-mentioned gene expression in LPS-treated adipocytes.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Anaesthesiology, Nanfang Hospital of Southern Medical University, Guangzhou, Guangdong 510515 China.
authors.forename: Xiaoqiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510120, China; Guangdong Province Key Laboratory of Electrophysiology and Arrhythmia, Guangzhou, Guangdong 510120, China.
authors.forename: Yongqin
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510120, China; Guangdong Province Key Laboratory of Electrophysiology and Arrhythmia, Guangzhou, Guangdong 510120, China.
authors.forename: Niansang
authors.initials: N
authors.lastname: Luo
authors.affiliation: Department of Anaesthesiology, Nanfang Hospital of Southern Medical University, Guangzhou, Guangdong 510515 China.
authors.forename: Zhongqing
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Anaesthesiology, Nanfang Hospital of Southern Medical University, Guangzhou, Guangdong 510515 China.
authors.forename: Miaoning
authors.initials: M
authors.lastname: Gu
authors.affiliation: Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510120, China; Guangdong Province Key Laboratory of Electrophysiology and Arrhythmia, Guangzhou, Guangdong 510120, China.
authors.forename: Jingfeng
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510120, China; Guangdong Province Key Laboratory of Electrophysiology and Arrhythmia, Guangzhou, Guangdong 510120, China. Email: tjcyx1995@163.com.
authors.forename: Yangxin
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects* / Q000276:immunology*; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D000069059:Atorvastatin; D006538:Heptanoic Acids / Q000627:therapeutic use*; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000276:immunology*; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D011758:Pyrroles / Q000627:therapeutic use*; D011817:Rabbits
chemical_list: D006538:Heptanoic Acids; D011758:Pyrroles; D000069059:Atorvastatin; D001094:Arachidonate 5-Lipoxygenase