Abstract
Multiple viruses are implicated in atherosclerosis, but the mechanisms by which they infect cells and contribute to plaque formation in arterial walls are not well understood. Based on reports showing the presence of enterovirus in atherosclerotic plaques we hypothesized that the coxsackievirus and adenovirus receptor (CXADR/CAR), although absent in normal arteries, could be induced during plaque formation. Large-scale microarray and mass spectrometric analyses revealed significant up-regulation of CXADR messenger RNA and protein levels in plaque-invested carotid arteries compared with control arteries. Macrophages were identified as a previously unknown cellular source of CXADR in human plaques and plaques from Ldr−/−Apob100/100 mice. CXADR was specifically associated with M1-polarized macrophages and foam cells and was experimentally induced during macrophage differentiation. Furthermore, it was significantly correlated with receptors for other viruses linked to atherosclerosis. The results show that CXADR is induced in macrophages during plaque formation, suggesting a mechanism by which enterovirus infect cells in atherosclerotic plaques.
Highlights
Enterovirus RNA has been isolated from atherosclerotic lesions [7] and is associated with an increased risk of developing unstable angina [8], and acute myocardial infarction [9]
Large-scale microarray analysis was performed to study the expression of CXADR messenger RNA (mRNA) in atherosclerotic plaques from patients with carotid stenosis (n = 127)
We found that CXADR staining in plaques colocalized with the macrophage marker CD68, suggesting that macrophages could represent a cellular source of CXADR in atherosclerotic plaques
Summary
Enterovirus RNA has been isolated from atherosclerotic lesions [7] and is associated with an increased risk of developing unstable angina [8], and acute myocardial infarction [9]. Enterovirus antigens were detected in 49% of patients with coronary heart disease and in 54.3% of those with myocardial infarction [10]. Experimental studies have shown that coxsackievirus B (CVB), a subspecies of the enterovirus family, can promote atherosclerosis in animal models [11], yet the mechanisms of how CVB and other enteroviruses target the plaque microenvironment are not clear. The coxsackievirus and adenovirus receptor (CXADR/CAR) is the high-affinity receptor for CVB and other subtypes of enteroviruses [12]. CXADR is not expressed in normal blood vessels, and its expression in atherosclerotic vessels has not been studied. CXADR belongs to the cortical thymocyte marker in CXADR in Atherosclerotic Plaques jid 2020:XX (XX XXXX) 1
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