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 4

Coronary plaque erosion and thrombosis in ApoE–/– mice after TAC.

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Coronary plaque erosion and thrombosis in ApoE–/– mice after TAC. (A) H&...
(A) H&E staining of sequential myocardial sections of ApoE–/– mice that died during the physical stress protocol. At 2.86 mm from AV (image 6), it is noticeable that the thrombus (light pink) is in contact with the coronary plaque of the LAD. Arrowhead indicates visible platelets. Scale bar: 50 μm. (B) Scheme of the localization of immunofluorescently labeled heart sections proximal and distal to the section at 2.86 mm from the AV. (C and D) IF staining of section proximal to erosion for Col I, CD41, αSMA, and Hoechst showed the absence of platelet aggregation. Hoechst staining shows the presence of elongated endothelial cell nuclei (C, i, arrowheads). (E) Schematic representation of the IF staining upstream the erosion shown in C and D. (F–I) IF for Col I, CD41, αSMA, and Hoechst of myocardial sections displaying the thrombus in the lumen, adjacent to but not inside the plaque (G, i). The fibrous cap (Col I and αSMA staining) adjacent to the thrombus is very thick and lacks of endothelial cell nuclei (I, i). (J) The staining for CD31 shows the presence of endothelial cells on the left side of the LAD free from platelet aggregates (J, i, arrows) but the absence of endothelial cells on the right side of the plaque in contact with the thrombus (J, ii, arrowheads). (K) Schematic representation of the IF staining of the eroded plaque with the thrombus in the LAD shown in H and J. Scale bars: 50 μm. (L) Masson’s trichrome staining of the medium and apex of the heart at the indicated distance from the AV. Scale bar: 1 mm.