Cholesterol Diet Withdrawal Leads to an Initial Plaque Instability and Subsequent Regression of Accelerated Iliac Artery Atherosclerosis in Rabbits

Abstract

Effect of long term cholesterol diet withdrawal on accelerated atherosclerosis in iliac artery of New Zealand White (NZW) rabbits has not been explored so far. Atherosclerosis was thus induced in rabbits by a combination of balloon injury and atherogenic diet (AD) (1% cholesterol and 6% peanut oil) feeding for 8 weeks (baseline) followed by chow diet (CD) feeding for 4, 8, 16, 32, 50 and 64 weeks. The plaque characterization was done using histology, real time RT-PCR and vasoreactivity studies. Significant elevation in plasma lipids with AD feeding was normalized following 16 weeks of CD feeding. However, baseline comparison showed advanced plaque features even after 8 weeks of CD period with significant elevation in intima/media thickness ratio and plaque area later showing reduction at 50 and 64 weeks CD periods. Lesion lipid accumulation and CD68 positivity was maintained till 16 weeks of CD feeding which significantly reduced from 32 to 64 weeks CD periods. Baseline comparison showed significant increase in ground substance, MMP-9 and significant decrease in α-actin and collagen content at 8 weeks CD period indicating features of unstable plaque. These features regressed up to 64 weeks of CD. Partial restoration of functional vasoconstriction and vasorelaxation was seen after 64 weeks of CD feeding. mRNA expression of MCP-1, VCAM-1, collagen type I and III, MMP-9, TIMP-1, IFN-γ, TNF-α, IL-10 and eNOS supported the above findings. The study thus reveals insights into initial plaque instability and subsequent regression on AD withdrawal in this model. These results are suggestive of an appropriate window for drug intervention for plaque stability/regression and restenosis as well as improves understanding of plaque regression phenomenon in this model.

Altered glucose and lipid homeostasis in liver and adipose tissue pre-dispose inducible NOS knockout mice to insulin resistance

“…Quantitative gene expression analysis was performed using SYBR Green as described previously65. Briefly, total RNA was extracted using TRIZOL reagent, and cDNA was synthesized using RevertAid H Minus first strand cDNA synthesis kit.…”

A novel diet‐induced murine model of steatohepatitis with fibrosis for screening and evaluation of drug candidates for nonalcoholic steatohepatitis

“…Macrophages activated by cholesterol play a very important role in inducing steatohepatitis or arteriosclerosis (in the form of foam cells) (Khanna et al. ). Many studies have shown that cholesterol significantly increases the levels of serum leptin, interleukin‐6, fibrosis, and liver alpha‐smooth muscle actin ( α ‐SMA) in mice fed a solid diet containing 0.2% cholesterol with 30% fat, and that dysregulated hepatic cholesterol homeostasis as well as accumulation of liver free cholesterol are involved in the pathogenesis of NAFLD/NASH (Arguello et al.…”

Hyaluronic acid-decorated reconstituted high density lipoprotein targeting atherosclerotic lesions

“…Immunohistochemistry for macrophage was adopted from our previous work and Khanna' research [10,32]. Firstly, paraffin-embedded aortas were segmented into 4 mm slices at 5 mm intervals, dewaxed and rehydrated.…”