Radiation-Induced Atherosclerotic Plaque Progression in a Hypercholesterolemic Rabbit: A Prospective Vulnerable Plaque Model?

Human observations provide rich soil for making hypotheses, but good animal models are essential for understanding the disease and to test treatment modalities. Currently, there is no standard animal model of vulnerable plaque; therefore, the purpose of this study is to develop a pathophysiologically relevant vulnerable plaque model. New Zealand White rabbits were fed with 1% hypercholesterolemic (HC) diet for 7 days, followed by balloon denudation of both the iliac arteries, and continued on 1% HC diet. Four weeks later, in 12 rabbits one of the iliac arteries was radiated (192-Ir, 15 Gy), and in five rabbits both the iliac arteries were sham treated. Following that, rabbits were fed with 0.15% HC diet. Four weeks later, arteries were processed for histomorphometry or immunohistochemistry. Serum cholesterol levels were similar in all the groups. In radiated arteries, plaque area was significantly larger (32% larger then in sham). Macrophage-positive area in radiated arteries was 2.4 times greater than the macrophage-positive area in the nonradiated arteries. The area positive for macrophages is also positive for metalloproteinases (MMP)-1. The extent of α-actin positive area was significantly less (2.3-fold) in radiated arteries. The atherosclerotic plaque developed in the current model is predominantly composed of macrophages expressing metalloproteinases with few smooth muscle cells (SMC)—a characteristic of vulnerable plaque. The animal model presented in this study can elucidate at least part of the mechanism of plaque vulnerability and could be used to test treatment modalities to test plaque stability.