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The Role of Plasma ACE2 and Angiotensin Peptides in Heart Failure and Coronavirus Disease

  • Author / Creator
    Wang, Kaiming
  • Background
    The discovery of angiotensin-converting enzyme 2 (ACE2) introduced an alternative protective arm of the renin-angiotensin system (RAS), the ACE2/Angiotensin 1-7 (Ang 1-7)/Mas receptor axis, to counterbalance the more renowned pathogenic angiotensin-converting enzyme (ACE)/Angiotensin II (Ang II)/AT1 receptor axis that predominates in disease states due to RAS hyperactivation. As a crucial endogenous regulator of the RAS, ACE2 possesses a catalytically active ectodomain exposed to the circulation that hydrolyzes various vasoactive peptides including, Ang II and angiotensin I (Ang I), generating Ang 1-7 and angiotensin 1-9 (Ang 1-9), respectively. Notably, ACE2 has garnered international attention as the cellular receptor for severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2, becoming one of the most researched and well-known human proteins. A soluble form of ACE2 is shed from the membrane through proteolytic cleavage by a disintegrin and metalloprotease 17 (ADAM17), resulting in diminished ACE2-mediated tissue protection under pathological conditions. We propose that the dysregulation of plasma angiotensin peptides and ACE2 is a molecular signature of cardiovascular and inflammatory diseases and can further serve as prognostic markers for adverse clinical outcomes in heart failure (Chapter 2) and coronavirus disease-2019 (Chapter 3).

    Methods and Results
    In Chapter 2, we prospectively enrolled 110 patients with heart failure from outpatient clinics and the emergency department to perform comprehensive profiling of circulating and equilibrium levels of plasma angiotensin peptides using liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques. We found that an elevation in the ratio between Ang 1-7 to Ang II, effector peptides of the protective and harmful axis of the RAS, respectively, served as an independent and incremental predictor of beneficial outcomes, better survival rate, and reduced hospitalization duration. Although multiple peptidases participate in the proteolytic processing of Ang 1-7 and Ang II, ACE2 is a direct regulator of the Ang 1-7/Ang II ratio, and its dysregulation contributes to RAS imbalance resulting in adverse clinical outcomes.
    In Chapter 3, we prospectively enrolled 242 consecutive patients admitted to hospital wards designated for COVID-19 or intensive care units to measure plasma soluble ACE2 and other established disease markers using enzyme-linked immunosorbent assay and angiotensin peptides through LC-MS/MS at admission and repeated sampling on day seven. We found that an upward trajectory in soluble ACE2 was independently associated with an increased risk of mortality and incidence of acute myocardial injury and circulatory shock. In contrast, patients who survived the COVID-19 hospitalization were characterized by a substantial reduction in soluble ACE2. Additionally, we found a prominent elevation in plasma Ang I and Ang 1-7 levels in patients with COVID-19 accompanied by downregulated plasma ACE activity at hospital admission, likely due to the extensive pulmonary vascular endothelial injuries during SARS-CoV-2 infections.

    Conclusions
    Heart failure and COVID-19 shares mutual disease pathophysiology in forms of dysregulation in ACE2 and the RAS. Importantly, plasma angiotensin peptide and soluble ACE2 levels can be effectively monitored through disease progression to facilitate a personalized biomarker-guided approach for risk stratification and the implementation of medical therapies against these conditions. Moreover, our data suggest a potential role of ADAM17 inhibition and the development of novel strategies to enhance the beneficial ACE2/Ang 1-7/Mas axis to improve patient outcomes in cardiovascular and inflammatory diseases.

  • Subjects / Keywords
  • Graduation date
    Fall 2022
  • Type of Item
    Thesis
  • Degree
    Master of Science
  • DOI
    https://doi.org/10.7939/r3-6gds-sh61
  • License
    This thesis is made available by the University of Alberta Library with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.