miRNAs, viruses and high blood pressure

You may have read earlier this week how human cytomegalovirus - a seriously common pathogen - was discovered to be a possible cause of high blood pressure. What you may not have heard about (or read), is the actual paper that these headlines refer to - see paper here. And, if you had, you may not have been so quick to jump to that same conclusion the media had for it was only a correlation - no causation was determined - but the results are nonetheless important, as you'll see below.

Human cytomegalovirus infected endothelial cell with various viral proteins fluorescently labelled. Does HCMV cause hypertension? http://www.princeton.edu/artofscience. By Joerg Schroeer

What is hypertension?

Hypertension - or high blood pressure - is a chronic disease with deadly implications, affecting an estimated one billion adults worldwide. Referred to as a global pandemic, if left unchecked, high blood pressure can result in terminal damage to both blood vessels and organs leading to stroke, heart attack or kidney failure. And, as if this weren't bad enough, it kills silently while if detected early enough it can be effectively controlled through various drug regimes and lifestyle changes.

 Two flavors of hypertension are currently recognized: essential - the most common sort (90%) and secondary, the more rarer form. The causes of secondary are well characterized and usually result from a number of acute illnesses, while the origins of essential are more difficult to determine. This most likely reflects the complex nature of the disease, which results from interactions from both genetic and environmental components; any one of these in isolation having little effect on its overall state.

Given its global importance, the factors predisposing to - or causing - essential hypertension are subject to intense research, making the identification of a viral origin of the disease all the more interesting.

What about the virus?

Typical herpesvirus (of which HCMV is a member) particle morphology. http://viralzone.expasy.org

HCMV, a member of the herpesvirus family of viruses (large, double-stranded DNA viruses with over one hundred genes) is an expert human pathogen. And, with 40% percent of the human population estimated to be infected with the virus, who can argue. Also based on seroprevalence, 80% of the elderly population are infected making it one serious human pathogen.

Following initial infection, HCMV has the ability to rapidly enter a latent state, persisting within specific cells inside your body. The usual cells are fibroblasts, endothelial cells and some white blood cells. From here, it will every-so-often re-activate itself and be shed in your saliva, ready to infect the next susceptible person. So once you get infected, you are always infected. Although it barely causes disease in those with fully functioning immune systems, the people who are immuno-compromised (neonates, AIDS sufferers, chemotherpy patients or the elderly) aren't so lucky, giving rise to calls to develop a vaccine.

How does one relate to the other?

Originally carrying out an investigation into the gene regulatory microRNA (miRNA) expression differences between Chinese patients with and without high blood pressure, the researchers soon discovered an obvious sign of HCMV infection in the form of a virally encoded miRNA.

Plasma miRNA expression levels in the Chinese study. Note the number of differentially regulated miRNAs. The group focus on hcmv-miR-UL112 (first from top left) although others could have been addressed.

Quantitatively determining the miRNA levels in blood samples, many miRNAs were up or down regulated but the group focused in on one in particular: hcmv-miR-UL112 - derived from HCMV that was shown to be highly expressed in those suffering from primary hypertension. These expression differences were thought to be down to endothelial cells within the blood sample, termed circulating endothelial cells. HCMV seropositivity as well as higher amounts of viral DNA, in general, was seen to be correlated with the high blood pressure group, especially when other factors were considered. This correlation was not seen with other common human viruses (Epstein-Barr and adenoviruses) suggesting a certain specificity.

How might HCMV cause hypertension?

Well this paper doesn't prove that one causes the other, only that HCMV infection and hcmv-miR-UL112 expression in particular significantly correlates with high blood pressure. There of course may and will be other factors influencing this, but in speculation, how may this miRNA influence disease pathology?

Scanning electron micrograph of a blood vessel - note red blood cells in red and endothelial cells in beige. How does HCMV influence the behavior of these cells?
Steve Gschmeissner / Photo Researchers Inc.

As I mentioned before, HCMV lies dormant inside the endothelial cells lining your blood vessels. Although latent, a number of genes are expressed from its genome specifically hcmv-miR-UL112, which helps it avoid detection by our bodies immune system. The researchers in this paper demonstrate an additional target for this molecule in Interferon Regulatory Factor 1 (IRF-1) a key regulator of the immune response and has been implicated in a number of vascular diseases (they list a dozen hypothetical mechanisms linking HCMV to hypertension.)

Although this paper did not provide conclusive evidence that HCMV causes high blood pressure (Koch's postulates were not fulfilled or even looked at), it does shine some light on the causes of essential hypertension - a long sought after goal. Further studies will need to validate these results in non-Chinese samples and investigate mechanisms in which latent and/or replicating HCMV can influence endothelial functioning in vivo.


Li S, Zhu J, Zhang W, Chen Y, Zhang K, Popescu LM, Ma X, Bond Lau W, Rong R, Yu X, Wang B, Li Y, Xiao C, Zhang M, Wang S, Yu L, Chen AF, Yang X, & Cai J (2011). Signature microRNA Expression Profile of Essential Hypertension and Its Novel Link to Human Cytomegalovirus Infection. Circulation, 124 (2), 175-84 PMID: 21690488