Matrix Metalloproteinase-13 in Atherosclerotic Plaque Is Increased by Influenza A Virus Infection

Abstract

Background Influenza virus infection triggers acute cardiovascular events. Several studies have demonstrated that influenza A virus infection was associated with immune cell influx and increased production of inflammatory cytokines in the atherosclerotic plaque lesion, but the underlying mechanism for these findings is not clear. Methods We examined the expression levels of matrix metalloproteinases (MMPs) by influenza A virus infection in human cells using quantitative real-time polymerase chain reaction, Western blot, and human MMP-13 enzyme-linked immunosorbent assay. In an animal study, protein expression in the plaque lesions of apolipoprotein E (ApoE)-deficient mice were analyzed by immunohistochemistry and Western blot. Results We confirmed that MMP-13 was increased in influenza A virus-infected cells. In the aorta of infected ApoE-deficient mice, MMP-13 was increased at 3 days after infection. Immunohistochemical staining results suggested that collagen was degraded in the MMP-13 expression area and that macrophages were the main source of MMP-13 expression. Furthermore, the expression of MMP-13 was regulated by influenza A virus through activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Conclusions In this study, we demonstrated that p38 MAPK-mediated MMP-13 expression by influenza A virus infection led to destabilization of vulnerable atherosclerotic plaques in the artery.

Immune Mechanisms in Cardiovascular Diseases Associated With Viral Infection

“…An in vitro study using HUVEC cells has shown that influenza virus infection increases the expression of MMP9. Another study has shown that the expression of MMP-13 is increased in the atherosclerotic plaques of Apoe -/mice infected with influenza A virus (129). These studies suggest that influenza virus infection-induced inflammatory mediators may increase plaque destabilization and rupture, leading to MI.…”

Metalloproteinases and Their Inhibitors: Potential for the Development of New Therapeutics

“…The correlation between the increase in the expression level of MMP-1, MMP-3, and MMP-12 and plaque instability and cardiovascular disease progression were demonstrated clearly [149]. In the cells infected with influenza a virus, an increase in MMP-13 within 3 days of infection was found [152]. MMP-13 expression, mediated by influenza a virus via p38 mitogen activated protein kinase, was found to destabilize the susceptible arterial plaques triggering cardiovascular events eventually [152].…”

Matrix Metalloproteinases as Biomarkers of Atherosclerotic Plaque Instability

“…Studies on human cells infected with influenza A virus showed an increase of MMP-13 expression, which may partly explain the destabilization of atherosclerotic plaques. Analysis of the corresponding changes in the ApoE-deficient mouse model has shown that the increase of MMP-13 expression is due to activation of the p38 mitogen-activated protein kinase signaling pathway [119]. Increased MMP-7 activity can be connected with the apoptosis of VSMCs in the fibrous cap and lesion destabilization [120].…”