Abstract
Cytomegalovirus (CMV) infection is a common infection in adults (seropositive 60–99% globally), and is associated with cardiovascular diseases, in line with risk factors such as hypertension and atherosclerosis. Several viral infections are linked to hypertension, including human herpes virus 8 (HHV-8) and HIV-1. The mechanisms of how viral infection contributes to hypertension or increased blood pressure are not defined. In this report, the role of CMV infection as a cause of increased blood pressure and in forming aortic atherosclerotic plaques is examined. Using in vivo mouse model and in vitro molecular biology analyses, we find that CMV infection alone caused a significant increase in arterial blood pressure (ABp) (p<0.01∼0.05), measured by microtip catheter technique. This increase in blood pressure by mouse CMV (MCMV) was independent of atherosclerotic plaque formation in the aorta, defined by histological analyses. MCMV DNA was detected in blood vessel samples of viral infected mice but not in the control mice by nested PCR assay. MCMV significantly increased expression of pro-inflammatory cytokines IL-6, TNF-α, and MCP-1 in mouse serum by enzyme-linked immunosorbent assay (ELISA). Using quantitative real time reverse transcriptase PCR (Q-RT-PCR) and Western blot, we find that CMV stimulated expression of renin in mouse and human cells in an infectious dose-dependent manner. Co-staining and immunofluorescent microscopy analyses showed that MCMV infection stimulated renin expression at a single cell level. Further examination of angiotensin-II (Ang II) in mouse serum and arterial tissues with ELISA showed an increased expression of Ang II by MCMV infection. Consistent with the findings of the mouse trial, human CMV (HCMV) infection of blood vessel endothelial cells (EC) induced renin expression in a non-lytic infection manner. Viral replication kinetics and plaque formation assay showed that an active, CMV persistent infection in EC and expression of viral genes might underpin the molecular mechanism. These results show that CMV infection is a risk factor for increased arterial blood pressure, and is a co-factor in aortic atherosclerosis. Viral persistent infection of EC may underlie the mechanism. Control of CMV infection can be developed to restrict hypertension and atherosclerosis in the cardiovascular system.
Highlights
Human cytomegalovirus (HCMV) is a member of the herpes virus family, and HCMV infection is ranked as one of the most common infections in adults, with the seropositive rates ranging from 60–99% globally
An increased angiotensin II (Ang II) level was detected in mouse serum and in arterial blood vascular tissues after mouse CMV (MCMV) infection. This is of great interest, since renin is known as a rate limiting protein of Renin-Ang-II system (RAS) and Ang II is the effector peptide that directly binds to blood vessels, causes vasoconstriction and leads to systemic hypertension in humans [24,25,26,27]
The experimental results show that MCMV infection alone significantly increased arterial blood pressure, compared to their counterparts in each control group (Fig. 1A–E, V-High cholesterol diet (HD) vs. HD; V vs. M)
Summary
Human cytomegalovirus (HCMV) is a member of the herpes virus family, and HCMV infection is ranked as one of the most common infections in adults, with the seropositive rates ranging from 60–99% globally. The infection with HCMV is associated with cardiovascular diseases, and some countries have reported low rates of HCMV seropositivity and a high incidence of atherosclerosis [1,2,3,4]. Several virus infections are associated with hypertension or an increase of blood pressure, including human herpesvirus 8 (HHV-8) and HIV-1 in primary pulmonary hypertension [5,6,7]. In a mouse model of pulmonary hypertension, a recent paper has explored the mechanism of pulmonary artery muscularization and arterial remodeling by inflammation and the Th2 immune response [8]. Clinical isolates of HCMV have been shown to infect endothelial cells, and the presence of HCMV antigens in endothelial cells triggers inflammation and immune response via secretion of CXC chemokines and recruiting neutrophils, which are infected by HCMV in the process of neutrophil transendothelial migration [9]
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