One of the benefits of working in the Abboud Cardiovascular Research Center (ACRC) is that researchers have ready access to collaborators. A publication earlier this year in the Journal of Allergy and Clinical Immunology shows the results of one such collaboration within the ACRC. The article both identifies a specific immune cell cytokine in hypertensive rats that impairs the normal relaxation of aortic vessels and a means of preventing it. Identifying this mechanism presents a potential therapeutic target in the treatment of human hypertension.
Dr. François Abboud and Dr. Madhu Singh have been studying the link between the immune system and high blood pressure. In fact, Dr. Singh points out, there is “evidence that hypertension may be considered as an autoimmune disease.” Though what happens at the cellular and molecular levels is less understood and thus the focus of Dr. Abboud and Dr. Singh’s work with spontaneously hypertensive rats (SHR). The benefit of using SHRs is their close resemblance to human hypertension, so the research team could look for changes in the immune cell populations of the SHRs from birth as they developed hypertension over time.
“We discovered an abnormally abundant population of immune cells in SHR spleen that express a CD161+ surface marker at birth,” Dr. Singh said. They then found a specific subset of this population contained unusually high amounts of a particular master regulator transcription factor RORgt that induces synthesis of the inflammatory cytokine interleukin-17F. Cytokines work like hormones but in very focused, localized ways, sending signals that often cause organ damage. They promote inflammation and have been linked to multiple sclerosis, Crohn’s disease, and lupus. IL-17F has not been previously linked to hypertension. But, Dr. Singh says:
Since hypertension is associated with vascular stiffness and inflammation, we surmised that the increased expression of IL-17F in SHRs might be causing inflammatory dysfunction of the blood vessels and resulting in hypertension. If this was true then treatment of normal blood vessels with IL-17F should cause functional defect, a loss of vasorelaxation in the standard experiments. To test this hypothesis, we sought help from our colleagues at the ACRC, Drs. Kaikobad Irani and Santosh Kumar. Indeed, treatment with IL-17F cytokine impaired the capacity of the aortic vascular smooth muscles to relax. Moreover, these effects were dependent on nitric oxide, a vasorelaxant that is released from the endothelium, a single layer of cells lining the blood vessels. Thus, IL-17F impaired the normal vasorelaxation of aortic vessels.
The research team did not stop there, but began to look for what determined the expression of the IL-17F cytokine and whether it could be suppressed. They began treating young SHRs with daily doses of digoxin, a known inhibitor of the RNA transcription factor RORgt producing the cytokine. As a preventive measure, these injections were successful in lowering the increase in blood pressure in the rats as they became older.
Other members of the ACRC, Dr. Mark Chapleau and Dr. David Meyerholz, were also part of this research team. As a nice post-script, many of those researchers enjoyed a nice meal together recently to celebrate the culmination of the work that this publication represents. Congratulations to all on a successful collaboration, discovery, and publication.