Abstract
Atherosclerosis is a progressive vascular wall inflammatory disease, and the rupture of atherosclerotic vulnerable plaques is the leading cause of morbidity and mortality worldwide. This study intended to explore the potential mechanisms behind plaque rupture and thrombosis in ApoE knockout mice. The spontaneous plaque rupture models were established, and left carotid artery tissues at different time points (1-, 2-, 4-, 6-, 8-, 12-, and 16-week post-surgery) were collected. By the extent of plaque rupture, plaque was defined as (1) control groups, (2) atherosclerotic plaque group, and (3) plaque rupture group. Macrophage (CD68), MMP-8, and MMP-13 activities were measured by immunofluorescence. Cytokines and inflammatory markers were measured by ELISA. The left carotid artery sample tissue was collected to evaluate the miRNAs expression level by miRNA-microarray. Bioinformatic analyses were conducted at three levels: (2) vs. (1), (3) vs. (2), and again in seven time series analysis. The plaque rupture with thrombus and intraplaque hemorrhage results peaked at 8 weeks and decreased thereafter. Similar trends were seen in the number of plaque macrophages and lipids, the expression of matrix metalloproteinase, and the atherosclerotic and plasma cytokine levels. MiRNA-microarray showed that miR-322-5p and miR-206-3p were specifically upregulated in the atherosclerotic plaque group compared with those in the control group. Meanwhile, miR-466h-5p was specifically upregulated in the plaque rupture group compared with the atherosclerotic plaque group. The highest incidence of plaque rupture and thrombosis occurred at 8 weeks post-surgery. miR-322-5p and miR-206-3p may be associated with the formation of atherosclerotic plaques. miR-466h-5p may promote atherosclerotic plaque rupture via apoptosis-related pathways.
Highlights
Atherosclerosis is a chronically progressive vascular wall inflammatory disease (Taleb, 2016)
Understanding the pathophysiological mechanism of plaque rupture is of significance for the prevention and treatment of acute cardiovascular and cerebrovascular diseases caused by atherosclerotic plaque rupture (Bentzon et al, 2014)
Unstable plaque morphology and rupture occurred after 4 weeks, and plaque rupture with thrombus and intraplaque hemorrhage peaked at 8 weeks
Summary
Atherosclerosis is a chronically progressive vascular wall inflammatory disease (Taleb, 2016). Multiple subclinical cellular events cause the development of vulnerable, unstable atherosclerotic lesions This leads to the rupture of atherosclerotic plaques and, to catastrophic clinical manifestation of ischemic stroke or myocardial infarction (Chen et al, 2016). A high incidence of spontaneous plaque rupture related to lumen thrombosis was generated successfully (Jin et al, 2012) This simple murine model (abbreviated as “R + C model”) recapitulated the pathophysiological processes of human plaque rupture and generated rapid plaque progression. The R + C model manifests the pathological characteristics of human plaques and demonstrates similar reactivity to existing atherosclerotic drugs This model may be useful for analyzing the mechanisms of action involved in atherosclerotic plaque instability
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