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A study of the roles of the immune and inflammatory systems in hypertension.

Periodic Reporting for period 2 - InflammaTENSION (A study of the roles of the immune and inflammatory systems in hypertension.)

Reporting period: 2018-11-01 to 2020-04-30

The overarching theme of the proposal Hypertension is a common disease impacting 1 billion people worldwide, which leads to catastrophic cardiovascular complications, including heart failure, dementia, myocardial infarction and stroke - all of which carry severe socioeconomic burden. In spite of many years of research, the cause of primary hypertension remains unknown and disease is uncontrolled in a large proportion of patients. By interrogating the key hypothesis that inflammatory dysregulation fundamentally controls development of hypertension and vascular remodelling, InflammaTENSION provides a new paradigm for the management of the disease, with the potential to lead to the identification of novel therapeutic targets to control blood pressure and limit target organ damage. InflammaTENSION will result in the discovery of novel biomarkers, which may identify patients who could benefit from such immune targeted therapies. Importantly, we already made the seminal observation that the immune system not only mediates target organ damage, b defined the roles of pro-inflammatory T cells, monocytes, as well as anti-inflammatory T regulatory cells in the disease process. However, our current knowledge remains very fragmented and so far has not been applied to human pathology. InflammaTENSION will for the first time advance the knowledge procured in rodent models into human studies.Over the course of the programme we will: (1) characterize the immunophenotypic signature of human hypertension; (2) define key concepts in cytokine biology of hypertension with TNF-alpha and IL-6 as key exemplars and (3) understand how chronic cytokines implicated in hypertension regulate the T cell dependent mechanisms of hypertension. InflammaTENSION will also go beyond current state-of-the-art through comprehensive combination of immunology and cardiovascular disease to create a new understanding of how the immune system may lead to human hypertension and vascular remodelling. Such a coordinated and integrative programme to better understand the role of dysregulation of the immune system in human hypertension will have major impact on the field, enabling translation of these exciting findings to clinical practice
While work on all of the aspects described in the objectives continue work performed from the beginning of the project to the end of current period allowed for a number of discoveries going beyond current state of the art:
1. We found that a small piece of genetic material could explain why arteries become increasingly stiff , which happens in high blood pressure and why blood vessels age faster in hypertension. If found in patient blood samples, this molecule could give doctors an early warning of artery problems, and help people get treatment more quickly. In this study we used many in vivo, in vitro as well as translational human approaches to identify how small molecule of microRNA that is present in lymphocytes, white blood cells responsible for fighting infections, can direct these cells to blood vessels. We pinpointed a piece of genetic material called a micro-RNA – specifically one called miR-214 - which makes white blood cells called T-cells move to the fatty tissue around arteries. Once in this tissue, the T-cells cause inflammation, causing the artery structure to become damaged and increasing their stiffness. This work is the first to link a cascade of damaging events linked to blood pressure to higher levels of miR-214. This is responsible, at least in part, for the process of accelerated vascular ageing characterized by stiffer vessels. We have shown this not only in disease models but also provided proof of concept in patients with hypertension. his work is the first to link a cascade of damaging events linked to blood pressure to higher levels of miR-214. The paper was featured in press release and in newspapers and tweets worldwide (e.g. https://news.cision.com/kidney-research-uk/r/new-research-gives-clues-to-artery-problems-in-high-blood-pressure,c3094985 ; AND: https://www.heraldscotland.com/news/18436383.new-treatment-silent-killer-horizon-scottish-scientists-make-major-breakthrough-high-blood-pressure/)
2. We observed that probably the most common inflammation in human body – periodontitis is causally linked to blood pressure control. We used a series of approaches starting from hypertension model studies, through a genetic study and clinical interventional trial reaching a systematic review and metanalysis style. These studies were received with very high interest by public, as have been picked up by 42 news outlets, blogged and tweeted by over 200, quoted on Facebook pages and referenced in Wikipedia. Our main paper has been widely discussed at conferences and also as podcasts (available on Spotify)
3. We have shown, using a large population analysis a clear link in humans between blood lymphocytes and blood pressure levels (using a large population of >7500000 people in the largest blood pressure genetic study). These studies provide in man, populational evidence supporting the main InflammaTENSION thesis that inflammation is essential in regulating blood pressure. This study has reached visibility through social media engagement by 2 main scientific societies in cardiology - American Heart Association as well as European Society of Cardiology.
In this project we are progressing beyond state of the art by combining clinical translational and model mechanistic studies it will identify novel inflammatory factors that can control immune mechanisms of hypertension. In detail, over the course of the programme we will: (1) characterize the immunophenotypic signature of human hypertension; (2) define key concepts in cytokine biology of hypertension with TNF-alpha and IL-6 as key exemplars and (3) understand how chronic cytokines implicated in hypertension regulate the T cell dependent mechanisms of hypertension. InflammaTENSION will also go beyond current state-of-the-art through comprehensive combination of immunology and cardiovascular disease to create a new understanding of how the immune system may lead to human hypertension and vascular remodelling. Such a coordinated and integrative programme to better understand the role of dysregulation of the immune system in human hypertension will have major impact on the field, enabling translation of these exciting findings to clinical practice.
In progress so far we have already provided comprehensive evidence supporting role of inflammation in hypertension using epidemiological and genetic tools as well as have shown proof of concept of using this knowledge in human therapy. We are working on identifying further specific novel mechanisms.
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