Date Published: March 21, 2018
Publisher: Public Library of Science
Author(s): Seul-Gee Lee, Jaewon Oh, Sung-Kyung Bong, Jung-Sun Kim, Seil Park, Sehoon Kim, Sungha Park, Sang-Hak Lee, Yangsoo Jang, Xianwu Cheng.
Atherosclerosis is a well-known cause of cardiovascular disease and is associated with a variety of inflammatory reactions. However, an adequate large-animal model of advanced plaques to investigate the pathophysiology of atherosclerosis is lacking. Therefore, we developed and assessed a swine model of advanced atherosclerotic plaques with macrophage polarization.
Mini-pigs were fed a 2% high-cholesterol diet for 7 weeks followed by withdrawal periods of 4 weeks. Endothelial denudation was performed using a balloon catheter on 32 coronary and femoral arteries of 8 mini-pigs. Inflammatory proteins (high-mobility group box 1 [HMGB1] or tumor necrosis factor alpha (TNF-α) were injected via a micro-infusion catheter into the vessel wall. All lesions were assessed with angiography and optical coherence tomography and all tissues were harvested for histological evaluation.
Intima/plaque area was significantly higher in the HMGB1- and TNF-α-injected groups compared to the saline-injected group (p = 0.002). CD68 antibody detection and polarization of M1 macrophages significantly increased in the inflammatory protein-injected groups (p<0.001). In addition, advanced atherosclerotic plaques were observed more in the inflammatory protein-injected groups compared with the control upon histologic evaluation. Direct injection of inflammatory proteins was associated with acceleration of atherosclerotic plaque formation with M1 macrophage polarization. Therefore, direct delivery of inflammatory proteins may induce a pro-inflammatory response, providing a possible strategy for development of an advanced atherosclerotic large-animal model in a relatively short time period.
Atherosclerosis is the primary cause of coronary and cerebrovascular disease, which is the leading cause of death worldwide . The advanced atherosclerotic process is a result of a complex inflammatory and immune response . High levels of low-density lipoprotein-cholesterol are associated with the accumulation of oxidized low-density lipoprotein in the vascular inner wall, which can trigger the formation of monocytes and their differentiation into macrophages in the arterial wall . Macrophages play a pivotal role in the development, progression, and rupture of atherosclerotic plaques.
Here, we found that direct injection of inflammatory proteins was associated with acceleration of atherosclerotic plaque formation in swine coronary and peripheral arteries, as well as increased macrophage infiltration in atheromatous plaques and induced macrophage polarization to the pro-inflammatory M1 subtype. Furthermore, advanced atherosclerotic plaques were more frequently observed in the inflammatory protein-injected groups compared with the control via OCT and histologic analysis. Based on our observations, direct delivery of inflammatory proteins can be an alternative strategy to develop a reproducible large animal model with advanced atherosclerotic plaques.