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Investigating the role of the renin angiotensin system in COVID19 patients


Bristol Medical School

About the Project

Rationale
The recent emergence of the COVID19 pandemic, caused by the SARS-CoV2 virus that gives rise to a variably symptomatic and sometimes life-threatening disease, has once again shown that as with the more limited SARS outbreak in the early 2000s, that the renin angiotensin system, in particular ACE2 plays a significant almost paradoxical role in both the uptake of the virus and the subsequent recovery from disease that may result (Touyz et al, 2020). Risk factors that have been identified with increased risk of severe SARS-CoV2-related disease include advancing age, obesity and type II diabetes, some forms of cardiovascular and renal disease, polymorphisms in APOE, and some ethnic minorities groups appear to be at higher risk. Many of these diseases have been linked or sometimes benefit from treatments that target the RAS profile of risk factors for COVID19 bears close resemblance to suggested risk factors for several forms of late-onset neurodegenerative diseases such as Alzheimer’s disease (AD).

It is therefore very notable that the activity of ACE2 appears to be a determinant in outcomes of these age-related diseases. In Alzheimer’s disease reductions in ACE2 activity at post mortem appear to correlate strongly with worse neuropathology (Evans et al, 2020), whilst higher levels of ACE2 activity, despite ACE2 being the receptor for the uptake of the SARS-CoV2 virus, appear vital for the recovery of people who develop severe respiratory disease when they succumb to COVID-19 (Wosten-den Asperen et al, 2012). We want to explore, using archival samples being collected in an ongoing observational DISCOVER study of COVID-19 patients admitted to hospital and followed up for a variety of disease outcomes, whether imbalance in key factors of the RAS are predictors of outcomes for COVID-19 patients.

Aims & Objectives
This multi-disciplinary study will investigate the extent of classical RAS activation versus that of the regulatory RAS, which includes ACE2, in relation to outcomes of COVID-19 patients.

We wish to test the following research questions in the first instance:
1. To what extent is there imbalance between ACE and ACE2 levels and activity in COVID-19 positive versus COVID-19 negative patients admitted to hospital?
2. Do levels and activity of ACE2, versus ACE correlate in blood sera and predict better clinical outcomes and rates of recovery for COVID-19 patients?

Methods
The study will use sera extracted from ~200 participants whom were diagnosed as COVID-19 positive and negative patients on admission to Southmead Hospital, Bristol, UK in 2020 and who were enrolled in a prospective observational DISCOVER study of COVID-19 patient outcomes. In the first instance the levels and enzyme activities of ACE and ACE2 will be measured using established ELISA’s and fluorogenic peptide substrate assays respectively. The ratio of ACE-1:ACE-2 activity will also be calculated to provide a proxy measure of RAS activation in this patient cohort, as we have used previously in other studies. Additional markers of RAS would also be measured and then the results of these experiments interrogated with the clinical outcomes data available from the DISCOVER project that is led by Drs Arnold and Hamilton.

References

Touyz RM et al. ACE2 the Janus-faced protein - from cardiovascular protection to severe acute respiratory syndrome-coronavirus and COVID-19. Clin Sci (Lond). 2020;134(7):747-50.

Evans CE et al. ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer's disease. Acta Neuropathol. 2020;139(3):485-502

Wosten-van Asperen RM et al. Acute respiratory distress syndrome leads to reduced ratio of ACE/ACE2 activities and is prevented by angiotensin-(1-7) or an angiotensin II receptor antagonist. J Pathol. 2011;225(4):618-27.

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