Abstract
AimsAtherosclerosis 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.MethodsMini-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.ResultsIntima/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.ConclusionDirect 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.
Highlights
Atherosclerosis is the primary cause of coronary and cerebrovascular disease, which is the leading cause of death worldwide [1]
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
Summary
Atherosclerosis is the primary cause of coronary and cerebrovascular disease, which is the leading cause of death worldwide [1]. Macrophages play a pivotal role in the development, progression, and rupture of atherosclerotic plaques. Rather than absolute size, determines whether atherosclerosis is clinically silent or pathogenic because unstable plaques can rupture, producing vessel-occluding thrombosis and end-organ damage. Stable plaques have a relatively thick fibrous cap, which consists largely of vascular smooth muscle cells (SMC) and extracellular matrix components, partitioning soluble clotting factors in the blood from thrombogenic molecules in the plaque [4]. Plaques destabilize when elevated local matrix metalloproteinase degrades and thins the fibrous cap, increasing the risk of lesion rupture and subsequent thrombosis [5]
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