Abstract
Although some features of plaque instability can be observed in genetically modified mouse models, atherothrombosis induction in mice has been attested to be difficult. We sought to test the hypothesis that alterations in blood thrombogenicity might have an essential role in the development of atherothrombosis in ApoE−/− mice. In a mouse model of plaque destabilization established in our laboratory, we targeted blood thrombogenicity by systemically overexpressing murine prothrombin via adenovirus-mediated gene transfer. Systemic overexpression of prothrombin increased blood thrombogenicity, and remarkably, precipitated atherothrombotic events in 70% of the animals. The affected plaques displayed features of culprit lesions as seen in human coronary arteries, including fibrous cap disruption, luminal thrombosis, and plaque hemorrhage. Treatment with aspirin and clopidogrel substantially reduced the incidence of atherothrombosis in this model. Mechanistically, increased inflammation, apoptosis and upregulation of metalloproteinases contributed to the development of plaque destabilization and atherothrombosis. As conclusions, targeting blood thrombogenicity in mice can faithfully reproduce the process of atherothrombosis as occurring in human coronary vessels. Our results suggest that blood-plaque interactions are critical in the development of atherothrombosis in mice, substantiating the argument that changes in blood coagulation status may have a determinant role in the onset of acute coronary syndrome.
Highlights
Metalloproteinase (MMP)-9 or urokinase[3,4,5,6]
In a mouse model of plaque destabilization established in our laboratory, we targeted blood thrombogenicity by systemically overexpressing murine prothrombin via adenovirus-mediated gene transfer (Fig. 1)
We showed that dual anti-platelet drug therapy substantially reduced the incidence of plaque disruption and atherothrombosis, indicating that this model may be potentially useful in preclinical drug developments
Summary
Metalloproteinase (MMP)-9 or urokinase[3,4,5,6]. features of plaque instability were observed in these mice, atherothrombotic events could not be consistently reproduced in these mice. Mainly intra-plaque hemorrhage, but not plaque disruption with concomitant thrombus, was observed in this model The mechanisms of this ‘atherothrombosis-resistance’ phenomenon in mice are poorly understood[2,9]. Welch et al reported that atherothrombosis was observed in about 20% of ApoE/Npc[1] double knockout mice, which might be related to increased thrombin generation and platelet activation due to Npc[1] deficiency[11]. In light of these findings, we hypothesized that alterations in blood thrombogenicity may be critical in the development of atherothrombosis in mouse models of plaque destabilization.
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