Pressure overload leads to coronary plaque formation, progression, and myocardial events in ApoE–/– mice
Alice Marino, Yi Zhang, Luisa Rubinelli, Maria Antonietta Riemma, James E. Ip, Annarita Di Lorenzo
Alice Marino, Yi Zhang, Luisa Rubinelli, Maria Antonietta Riemma, James E. Ip, Annarita Di Lorenzo
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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 3

Coronary plaque rupture and thrombosis in the LAD of TAC-operated ApoE–/– mice.

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Coronary plaque rupture and thrombosis in the LAD of TAC-operated ApoE–/...
Sequential myocardial histology of TAC-operated ApoE–/– mice that died during physical stress protocol. (A) H&E staining of myocardial sections showing the LAD. At 2.95 mm from the AV there are 2 major lesions and a thrombus (light pink) juxtaposed to the plaque on the right (asterisks, image 4, and i). (i) Magnified image of the thrombus with visible platelets (arrowheads) and red blood cells confined in a narrow lumen space. (B) Scheme of the localization of immunofluorescently stained myocardial sections proximal and distal to the thrombus shown in A, image 4. (C) IF staining of the LAD for collagen type I (Col I, green) and Hoechst (nuclei, blue), showing a thin and continuous fibrous cap on the left plaque (i) and a thin and discontinuous fibrous cap of the right plaque (ii). The 2 ruptured points are indicated by 2 arrowheads. (D) IF staining for CD41 (platelets, red), αSMA (smooth muscle cells, green), and Hoechst (blue) shows luminal thrombus juxtaposed to the left plaque (i). In ii, the thrombus is present in front of and within the right-ruptured plaque (arrowheads and dotted line). (E) Schematic representation of the IF staining in D and F of the ruptured plaque and thrombus in the LAD. (F) CD41, αSMA, and Hoechst IF staining of proximal consecutive section of the LAD, showing the same pattern of thrombus distribution in the lumen and within the ruptured plaque. (G) Schematic representation of the IF staining in H of the ruptured plaque and thrombus in the LAD. (H) Consecutive distal sections showing platelet infiltration and aggregation deeper into the plaque. Part of the right plaque detached from the arterial wall (dotted line). (I) IF staining for CD31 (EC) and αSMA of a consecutive distal section showing CD31-positive staining only in the upper left corner of the LAD, whereas is absent in the remaining LAD, where the ruptured plaque material and clots broke away from the wall. (J) Schematic representation of the IF staining in I of the disrupted endothelium in the LAD. (K) Masson’s trichrome staining of the medium and apex of the heart at the indicated distance from the AV. Scale bars: 50 μm.