Pressure overload leads to coronary plaque formation, progression, and myocardial events in ApoE–/– mice
Alice Marino, … , James E. Ip, Annarita Di Lorenzo
Alice Marino, … , James E. Ip, Annarita Di Lorenzo
Published May 2, 2019
Citation Information: JCI Insight. 2019;4(9):e128220. https://doi.org/10.1172/jci.insight.128220.
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Research Article Cardiology Vascular biology

Pressure overload leads to coronary plaque formation, progression, and myocardial events in ApoE–/– mice

Abstract

Hypercholesterolemia and hypertension are two major risk factors for coronary artery diseases, which remain the major cause of mortality in the industrialized world. Current animal models of atherosclerosis do not recapitulate coronary plaque disruption, thrombosis, and myocardial infarction occurring in humans. Recently, we demonstrated that exposure of the heart to high pressure, by transverse aortic constriction (TAC), induced coronary lesions in ApoE–/– mice on chow diet. The aim of this study was to characterize the magnitude and location of coronary lesions in ApoE–/– mice after TAC and to assess the susceptibility of coronary plaque to disruption, leading to myocardial events. Here, we describe a reliable pathological condition in mice characterized by the development of coronary lesions and its progression, leading to myocardial infarction; this model better recapitulates human disease. Following TAC surgery, about 90% of ApoE–/– mice developed coronary lesions, especially in the left anterior descending artery, with 59% of the mice manifesting a different magnitude of LAD stenosis. Myocardial events, identified in 74% of the mice, were mainly due to coronary plaque thrombosis and occlusion. That TAC-induced development and progression of coronary lesions in ApoE–/– mice, leading to myocardial events, represents a potentially novel and important tool to investigate the development of coronary lesions and its sequelae in a setting that better resemble human conditions.

Authors

Alice Marino, Yi Zhang, Luisa Rubinelli, Maria Antonietta Riemma, James E. Ip, Annarita Di Lorenzo

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Figure 1

Characterization and distribution of coronary lesions in ApoE–/– mice after TAC.

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Characterization and distribution of coronary lesions in ApoE–/– mice af...
(A) Scheme of the experimental design. Transverse aortic constriction (TAC) was performed in male ApoE–/– mice (~25 g of body weight) on chow diet, followed by histological, echocardiographic, and electrophysiological analysis at different time points after TAC. (B) At 8 weeks after TAC, sequential myocardial sections were stained with Oil Red O (binding to lipids) and hematoxylin and immunofluorescently stained with αSMA (SMCs), CD68 (monocyte/macrophages), and Hoechst (nuclei). Oil Red O showed lipid accumulation in the vascular wall, including endothelial cells (ECs), SMCs, and macrophages, of early and advanced coronary lesions. Consecutive heart sections immunofluorescently labeled showed macrophage (green) infiltration into the intima (white arrows) and media (white arrowheads) of the coronary arteries Scale bar: 50 μm. (C) Representative images of the coronary plaques in the LAD of 8-week TAC-operated ApoE–/– mice at different distance from the aortic valve (AV) showed different degree of stenosis. Scale bar: 50 μm. (D) Quantification of LAD stenosis from the AV to the apex of 8-week TAC-operated ApoE–/– mice (n = 10). (E) Base-to-apex lipid accumulation in the same LAD lesions, expressed as a percentage of the plaque area (n = 10). (F) Cartoon of the hot spot occurrence in coronary plaques. (G) Total plasma cholesterol levels of WT (n = 5), sham-operated, and TAC ApoE–/– mice (n = 8 and 20, respectively; plasma were collected between 1 and 11 weeks after surgery). (H) The pie chart shows the percentage of ApoE–/– mice with no lesions, early lesions with no stenosis, and coronary lesions with stenosis (n = 34). ***P < 0.001, 1-way ANOVA.