A new study suggests for the first time that cytomegalovirus (CMV), a common viral infection affecting between 60 and 99% of adults worldwide, is a cause of high blood pressure, according to researchers who performed the study.
Led by researchers at Beth Israel Deaconess Medical Center (BIDMC), Boston, a teaching hospital of Harvard Medical School, and published in the May 15, 2009 issue of PLoS Pathogens, the findings also show that in conjunction with other risk factors the virus can lead to the development of atherosclerosis, or hardening of the arteries.
A member of the herpes virus family, CMV affects all age groups and is the source of congenital infection, mononucleosis, and severe infection in transplant patients, according to the researchers, who say that by the age of 40, most adults will have contracted the virus, though many will never exhibit symptoms. Once it enters the body, CMV usually remains latent in the body until the immune system is compromised, they say.
Previous epidemiological studies had determined that the CMV virus was linked to restenosis in cardiac transplant patients, and atherosclerosis, but the mechanism behind these findings remained a mystery, the researchers say. This new study brought together a team of researchers from a variety of disciplines—infectious diseases, cardiology, allergy and pathology—to look at the issue.
In the first part of their studies, the scientists looked at four separate groups of laboratory mice. A control group of healthy mice were fed a standard diet; the second group, also fed a standard diet, was infected with the CMV virus after 4 weeks; the third group consisted of healthy mice fed a diet high in cholesterol; and the fourth group of mice were fed the high-cholesterol diet and then infected with CMV after 4 weeks.
Six weeks following infection with the CMV virus, the animals’ blood pressure was measured using a small catheter inserted in the mouse carotid artery used by research team in the Cardiology Division, the researchers say.
The results were very distinct, notes Crumpacker. “The CMV infection was found to cause an increase in blood pressure by itself and exacerbate the effect of a high cholesterol diet and obesity on high blood pressure,” he explains. The mice with the highest increase in blood pressure were those that were both infected with CMV and were fed a high cholesterol diet and this group had evidence of Atherosclerosis in 30% of mice. This suggests that CMV infection and high cholesterol diet might work together to cause high blood pressure and atherosclerosis.
“There was no question that CMV is able to lead to an increase in blood pressure by itself,” says Crumpacker. “But the exact mechanisms are not clear.” So, the investigators went on to conduct a series of measurements in the animals and cell culture experiments to answer the question.
Their first analysis demonstrated that CMV stimulated production of three different inflammatory cytokines – IL6, TNFµ, and MCP1 – in the infected mice. This discovery indicates that the virus is causing inflammation to vascular cells and other tissues, according to Crumpacker.
A second analysis then found that introduction of the virus in mice led to an increase in an enzyme, renin, which has been known to activate the renin-angiotensin system and lead to high blood pressure. Clinical isolates of human CMV in cultured blood vessel cells also produced increased renin expression.
“Viruses have the ability to turn on human genes and, in this case, the CMV virus is enhancing expression of renin, an enzyme directly involved in causing high blood pressure,” says co-senior author Clyde Crumpacker, MD, an investigator in the Division of Infectious Diseases at BIDMC and professor of Medicine at Harvard Medical School. When HCMV was inactivated by UV light no increase in renin was observed; therefore, replicating CMV was needed to enhance renin expression, say the researchers.
Their final experiments demonstrated that a second enzyme—angiotensin 11, was increased in the mice in response to infection with CMV. “It appears that a persistent CMV infection in these endothelial cell is required to cause high blood pressure in mice and enhance renin expression in tissue culture,” Crumpacker says.
“We found that CMV infection alone led to an increase in blood pressure. When combined with a high-cholesterol diet, the infection actually induced atherosclerosis—hardening of the arteries—in a mouse aorta,” he says. This suggests that further research needs to be directed at viral causes of vascular injury. Some cases of hypertension might be treated or prevented by antiviral therapy or a vaccine against CMV, according to the researchers.
This study was funded by grants from the National Institutes of Health.
Study co-authors include Jielin Zhang of BIDMC’s Division of Infectious Diseases (co-senior author); Jilin Cheng formerly of BIDMC’s Division of Infectious Diseases and now at Fudan University, Shanghai, China (first author); Qingen Ke of BIDMC’s Division of Cardiology; Zhuang Jin and Haiban Wang of BIDMC’s Division of Allergy; Olivier Kocher of BIDMC’s Division of Pathology; and James Morgan of Caritas St. Elizabeth’s Medical Center, Boston.