Atherosclerotic Plaque rupture in Apolipoprotein e−/− Mice

A therosclerotic plaque rupture and subsequent thrombus formation in the culprit lesion are recognized to be the seminal events in the majority of cases of acute coronary syndrome. Plaque stability is determined by many factors, including lipid deposits, oxidative stress, inflammation, and extracellular matrix degradation. Accumulation of lipid in the atherosclerotic lesion increases mechanical stress within the fibrous cap. 5 In addition, modification of low-density lipo-protein (LDL) by oxidative stress results in the avid uptake of these lipoproteins via infiltrating macrophages, which induces macrophage activation and foam cell formation. 6 The activation of macrophages in atherosclerotic plaques leads to the secretion of inflammatory cytokines and proteolytic enzymes capable of degrading the extracellular matrix, and these changes consequently increase plaque vulnerability. 7 Angiotensin II (Ang II) is well known to mediate cardio-vascular disease pathogenesis by regulating oxidative stress, inflammation, and cell proliferation. We previously demonstrated that the angiotensin II type 1a (AT 1a) receptor enhances neointimal formation after cuff-induced vascular injury as well as high-fat diet–induced atherosclerotic lesion formation in apolipoprotein E (ApoE) −/− mice, and that the AT 2 receptor counterregulates AT 1a receptor-mediated lesion formation. 8–11 However, the role of the AT 1a receptor in atherosclerotic plaque rupture is poorly understood. In a previous study, we demonstrated that expression of the AT 1a receptor in athero-sclerotic lesions was increased by feeding a high-cholesterol diet to ApoE −/− mice. 10 Ang II receptor blockade significantly inhibited lipid accumulation and oxidative stress in the ath-erosclerotic lesions of ApoE −/− mice fed a high-cholesterol diet. Moreover, Ang II receptor deletion prevents vascular oxidative stress, endothelial dysfunction and atherosclerotic lesion formation in ApoE −/− mice, irrespective of blood pressure and plasma cholesterol levels. 12 These results suggest that the AT 1a receptor may play a critical role in atherosclerotic plaque vulnerability. Several models of plaque rupture in ApoE −/− mice have been used for investigating the mechanisms responsible for plaque vulnerability. These models have included chow feeding for about a year, 13 high-fat feeding for about 2 months, 14 and cuff placement and subsequent adenovirus-mediated transfer of p53. 15 Recently, carotid artery ligation and cuff placement in ApoE −/− mice was shown to be a simple and highly efficient method of inducing plaque rupture. Objective—Angiotensin II is involved in the genesis of atherosclerosis. As the role of the angiotensin II type 1a (AT 1a) receptor in plaque rupture is poorly understood, we assessed …