title: Progression and Characterization of the Accelerated Atherosclerosis in Iliac Artery of New Zealand White Rabbits: Effect of Simvastatin.
abstract: OBJECTIVE
  Although atherosclerosis is described in New Zealand White rabbit's iliac artery, yet details of time-dependent atherosclerosis progression are not well known. Further, a well characterized accelerated model of atherosclerosis is also required for the screening of candidate drugs to target specific steps of atherosclerosis development. The present study extensively characterizes the time-dependent plaque composition and functional responses of the atherosclerosis in rabbit iliac artery and its modification by simvastatin.
  
  
  METHODS
  Atherosclerosis was induced with a combination of balloon injury and atherogenic diet (AD) (1% cholesterol, 6% peanut oil) in rabbit's iliac artery. Atherosclerosis progression was evaluated on days 8, 10, 15, 21, 35, and 56 after AD feeding. The plaque characterization was done using histology, real-time reverse transcription-polymerase chain reaction, and vasoreactivity experiments. The standard anti-hyperlipidemic drug, simvastatin (5 mg·kg·d), was used to investigate its effect on atherosclerotic changes.
  
  
  RESULTS
  Plasma lipids were elevated in a progressive manner after AD feeding from days 8 to 56. Similarly, arterial lipids, Monocyte Chemoattractant Protein-1 (MCP-1) level along with infiltration of macrophages in the lesion area were also increased from day 15 onward. This resulted in a significant increase in the plaque area and intimal-medial thickness ratio in contrast to normal animals. Inflammatory milieu was observed with a significant increase in expression of pro-inflammatory regulators like MCP-1, Tumor Necrosis Factor-α (TNF-α) and Vascular Cell Adhesion Molecule-1 (VCAM-1), whereas anti-inflammatory cytokine interleukin 10 decreased as disease progressed. Endothelial dysfunction was also observed, specifically Acetylcholine (ACh)-induced vasorelaxation was reduced from day 8 onward, whereas the phenylephrine-induced vasoconstriction response was progressively reduced from day 15 in the iliac artery. Ground substances including proteoglycans, α-actin, and collagen content along with metalloproteinase-9 and Tissue inhibitor of metalloproteinases-1 (TIMP-1) inhibitors were significantly augmented at later time points, day 21 onward. Simvastatin treatment for 35 days, at a dose having no significant effect on plasma lipid levels, significantly reduced atherosclerotic progression as evident by reduced macrophage content, inflammatory burden, and extracellular matrix component like proteoglycans and metalloproteinase-9.
  
  
  CONCLUSIONS
  The authors observed that AD feeding with balloon injury in the rabbit iliac artery accelerated the progression of atherosclerosis and exhibited predominant features of type III human lesion within 8 weeks (56 days). Simvastatin treatment for 35 days exhibited anti-atherosclerotic efficacy without significantly lowering the circulating lipids. The current study thus provides an insight into the time-dependent atherosclerotic progression in rabbit iliac artery and highlights its utility for anti-atherosclerotic evaluation of the candidate drugs.
authors.affiliation: Pharmacology Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India.
authors.forename: Jitendra S
authors.initials: JS
authors.lastname: Kanshana
authors.forename: Vivek
authors.initials: V
authors.lastname: Khanna
authors.forename: Vishal
authors.initials: V
authors.lastname: Singh
authors.forename: Manish
authors.initials: M
authors.lastname: Jain
authors.forename: Ankita
authors.initials: A
authors.lastname: Misra
authors.forename: Sachin
authors.initials: S
authors.lastname: Kumar
authors.forename: Mariya
authors.initials: M
authors.lastname: Farooqui
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Barthwal
authors.forename: Madhu
authors.initials: M
authors.lastname: Dikshit
mesh_terms: D000800:Angioplasty, Balloon; D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D015415:Biomarkers / Q000097:blood; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D005109:Extracellular Matrix / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007083:Iliac Artery / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000097:blood; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D058226:Plaque, Atherosclerotic; D011817:Rabbits; D019821:Simvastatin / Q000494:pharmacology*; D013997:Time Factors; D066253:Vascular Remodeling / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D015415:Biomarkers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018836:Inflammation Mediators; D008055:Lipids; D019821:Simvastatin