Ezetimibe reduces plaque inflammation in a rabbit model of atherosclerosis and inhibits monocyte migration in addition to its lipid‐lowering effect

Abstract

Background and purpose: Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, might also suppress inflammatory components of atherogenesis. We have studied the effects of ezetimibe on two characteristics of atherosclerotic plaques (infiltrate and fibrosis) and on expression of inflammatory genes in a rabbit model of accelerated atherosclerosis. Experimental approach: Femoral atherosclerosis was induced by a combination of endothelial desiccation and atherogenic diet. Animals were randomized to ezetimibe (0.6 mg·kg), ezetimibe plus simvastatin or no treatment, still on atherogenic diet. A control group of rabbits received normolipidemic diet. Key results: Rabbits fed the normolipidemic diet showed normal plasma lipid levels. Either the normolipidemic diet or drug treatment reduced the intima/media ratio (normolipidemic diet: 22%, ezetimibe: 13%, simvastatin: 27%, ezetimibe + simvastatin: 28%), compared with rabbits with atherosclerosis. Ezetimibe also decreased macrophage content and monocyte chemoattractant protein-1 expression in atherosclerotic lesions. Furthermore, ezetimibe reduced the increased activity of nuclear factor kB in peripheral blood leucocytes and plasma C-reactive protein levels in rabbits with atherosclerosis. In THP-1 cells, ezetimibe decreased monocyte chemoattractant protein-1-induced monocyte migration. Importantly, the combination of ezetimibe with simvastatin was associated with a more significant reduction in plaque monocyte/macrophage content and some proinflammatory markers than observed with each drug alone. Conclusions and implications: Ezetimibe had beneficial effects both on atherosclerosis progression and plaque stabilization and showed additional anti-atherogenic benefits when combined with simvastatin. Its effect on monocyte migration provides a potentially beneficial action, in addition to its effects on lipids.

A Human-Type Nonalcoholic Steatohepatitis Model with Advanced Fibrosis in Rabbits

“…cDNAs were synthesized with 1 g of total RNA, ReverTra Ace (Toyobo, Osaka, Japan), and oligo(dT) [12][13][14][15][16][17][18] primers according to the manufacturer's instructions. 23 Gene expression was measured by real-time PCR on an Applied Biosystems Prism 7500 system (Applied Biosystems, Foster City, CA) using cDNA, real-time PCR Master Mix Reagents (Toyobo), a set of gene-specific oligonucleotide primers, and the TaqMan probes listed in Table 1.…”

“…[11][12][13][14][15] It decreases the serum levels of low-density lipoprotein cholesterol and triglycerides (TGs) in humans 16 and reduces plaque formation and improves lipids in a rabbit model of atherosclerosis. 17 Recent reports have indicated that ezetimibe improves liver steatosis and insulin resistance in Zucker obese fatty rats 18 and rats fed a methionine-and choline-deficient diet. 19 Thus, ezetimibe is a potential new therapeutic agent for human NASH.…”

Age may determine the effect of hypolipidemic agents on plasma adipokine levels in patients with elevated low-density lipoprotein cholesterol levels

“…This cross-talk may change with age as a result of increased macrophage infiltration of adipose tissue [10]. Interestingly, monocyte-derived macrophage express NPC1L1 and other proteins bound by ezetimibe (amino peptidase N, annexin-2, and caveolin-1) [31,32], while ezetimibe was found to reduce the number of monocytes and the expression of monocyte chemoattractant protein-1 (MCP-1) in atherosclerotic plaques in rabbits [33]. It is possible that age-related changes in the number and function of macrophages may, at least partially, contribute to the different effect of ezetimibe in various age groups.…”

Ezetimibe suppresses cholesterol accumulation in lipid-loaded vascular smooth muscle cells in vitro via MAPK signaling

“…The beneficial effect of ezetimibe on the development of atherosclerosis was first shown in apolipoprotein E-deficient mice fed with a highfat diet [5] . Similarly, ezetimibe reduced atherosclerotic lesion formation in a diet-induced atherosclerosis model in hypercholesterolemic rabbits [6] . However, the exact anti-atherosclerotic mechanism of ezetimibe remains to be elucidated.…”