Cytomegalovirus Infection Causes an Increase of Arterial Blood Pressure

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.

Vascular dysfunction in young, mid-aged and aged mice with latent cytomegalovirus infections

“…These results are consistent with other studies showing that angiotensin II (6) and bradykinin (17) are up-or downregulated during an active CMV infection, respectively, and induce a hypertensive phenotype (6). Mesenteric arteries from young and mid-aged latently mCMV-infected mice had minimally but significantly reduced ME-induced endothelium-dependent vasodilation similar to previous findings in cremaster arteries in a model of persistent mCMV infection (28).…”

“…and CMV infections (6,14,17,19,28,31) are associated with increased blood pressure, vascular stiffness, and vascular dysfunction. The systemic vasculature in aging may compensate for the combined insults of aging and infection with increased endothelium-dependent vasodilation, even in the presence of a latent, not active, mCMV infection (12).…”

“…Vascular resistance and systemic blood pressure are impacted by the mesenteric vasculature. In our previous studies we showed an overall increase in vasodilation in mesenteric arteries isolated from mice actively infected with mCMV (14), which may be to compensate for increased vasoconstrictory activity (6,12,13). It is unknown whether these effects in mesenteric arteries are maintained during mCMV latency and whether the additional stress of aging would reduce the mCMV-mediated increase in vasodilation allowing vasoconstrictory effects to increase vascular tone.…”

Circulating microRNAs as diagnostic biomarkers for cardiovascular diseases

“…A possible causal link between HCMV and blood pressure is recently found in mice, where infection with mouse HCMV resulted in higher blood pressure (8). However, as indicated by Li et al (28), a high degree of interpatient variation was detected in miRNA levels in plasma, which will make it difficult to use these miRNAs as biomarkers for hypertension.…”

Characteristics of Human Cytomegalovirus specific T-Cells in Glioblastoma Multiforme

“…In this model, persistent HCMV infection of vascular endothelial cells resulted in viral expression without a cytopathic effect. This results in production of cytokines and renin and thus hypertension [113]. In a tumour this chronic infection is proposed to lead to expression of HCMV genes that induce production of cytokines that may contribute to oncogenesis or interact with the cell cycle to cause disruption to normal regulatory mechanisms.…”