Developing useful animal model for investigating the pathophysiological mechanisms of human plaque rupture

我们开发了人类斑块破裂的小鼠模型，该模型简单、快速、高效。将雄性载脂蛋白E（apoE）缺陷小鼠的左颈总动脉在其分叉近端结扎。在标准饮食4周后，小鼠在结扎部位近端接受聚乙烯套囊放置。在apoE缺陷小鼠中结扎颈动脉4周可诱导显著的内膜增生，这是一种富含脂质和胶原的病变，含有大量巨噬细胞、T淋巴细胞和平滑肌细胞。随后，袖带放置诱发斑块内出血和斑块破裂，该区域出现纤维蛋白（原）阳性管腔血栓，并伴随胶原蛋白含量减少以及白细胞、中性粒细胞和内膜凋亡细胞在袖带放置后几天内增加。血管壁MMP-2、MMP-3、MMP-9、MMP-14 mRNA水平在袖套置入后均升高。TIMP-2 mRNA水平下降。在该模型中观察到的这些事件似乎类似于人类斑块破裂的某些部分中的事件。我们相信，我们的模型是有用的，为调查的病理生理机制的发展，脆弱的病变和斑块破裂的人。此外，这种斑块破裂模型将有助于我们不仅了解人类斑块破裂的机制，而且在未来评估各种已知和未知的药物。事实上，3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂的给药防止了该模型中的斑块破裂。

We developed the murine model of human plaque rupture, which is simple, fast, and highly efficient. The left common carotid arteries of male apolipoprotein E (apoE)-deficient mice were ligated just proximal to their bifurcations. After 4 weeks on a standard diet, the mice received polyethylene cuff placement just proximal to the ligated site. Ligation of the carotid artery in apoE-deficient mice for 4 weeks induced marked intimal hyperplasia, which is a lipid-and collagen-rich lesion that contains a number of macrophages, T lymphocytes, and smooth muscle cells. Subsequently, the cuff placement evoked intraplaque hemorrhage and plaque rupture with fibrin(ogen)-positive luminal thrombus in this region accompanying a decrease in collagen content as well as an increase in leukocytes, and neutrophils, and apoptotic cells in the intima within a few days after cuff placement. MMP-2, MMP-3, MMP-9, MMP-14 mRNA levels in vascular wall increased after cuff placement. In contrast, mRNA level of TIMP-2 decreased. These events observed in this model appear to be analogous to the events in some parts of human plaque rupture. We believe that our model is useful for investigating the pathophysiological mechanisms underlying the development of the vulnerable lesion and plaque rupture of humans. In addition, this plaque rupture model will help us not only to understand the mechanism of human plaque rupture but also to assess various already-known and as-yet unknown agents in the future. In fact, administration of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor prevented the plaque rupture in this model.