Determining the role of IL-33 and ST2 in hypertension and vascular dysfunction

Saju, Blessy (2024) Determining the role of IL-33 and ST2 in hypertension and vascular dysfunction. PhD thesis, University of Glasgow.

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Cardiovascular disease (CVD) has long been the leading cause of global morbidity and mortality, largely due to deaths caused by stroke, heart failure (HF), hypertensive heart disease, peripheral arterial disease. Hypertension is defined as levels of blood pressure at which the benefits of treatment unequivocally outweigh the risk of treatment, by which systolic blood pressure values are ≥ 140 mmHg and/or diastolic blood pressure values are 90 ≥ mmHg in younger, middle-aged, and older people. Hypertension is characterised by cardiac and vascular irregularities in structure and function, causing end-organ vascular, heart, kidney, and additional end-organ damage, triggering cardiovascular complications such as myocardial infarction and stroke, heart, and renal failure.

Interleukin-33 (IL-33), a member of the IL-1 cytokine family, is believed to play essential roles in different cardiovascular diseases by binding to its specific receptor suppressor of tumorigenicity 2 (ST2). IL-33, through ST2, has demonstrated a capacity to influence cells of both the vascular and immune systems in healthy conditions and various cardiovascular pathologies, including atherosclerosis. There is curiosity about its potential role in hypertension and how it may be viewed as a potential therapeutic target. While the influence of IL-33 and ST2 has been examined in other aspects of CVD, little is known about its potential role in hypertension pathology. Thus, this thesis aims to test my hypothesis that the IL-33/ST2 axis plays a role in hypertension pathology. I propose that IL-33 is an alarmin molecule upon cell injury and signals the immune system in hypertension and associated target organ damage.

In the context of hypertension, I have demonstrated the upregulation of IL-33 and ST2 in several key organs involved in the disease, particularly the aorta. In addition, I have shown that IL-33 and ST2 are predominantly localised in the vascular endothelium and media of Angiotensin II-induced hypertensive mouse aorta. Furthermore, through the examination of healthy and vascular disease pathology, expression of IL-33 was confined to non-immune cells, and ST2 had key expression in immune cells of the aorta, with marked expression in the ILC2s (type 2 innate lymphoid cells) and mast cells. These data suggest that IL-33 and ST2 may influence hypertension pathology.

Using an inducible hypertension model in global IL-33 knock-out (IL-33-/-) and ST2 knock-out mice (ST2-/-) allowed us to assess the functional role of IL-33 and ST2 individually. Upon Ang II-induced hypertension, ST2-/- mice presented protection from periaortic collagen accumulation, a hallmark of hypertension pathology and regulated vascular dysfunction independently of blood pressure. Basally in the heart and in Ang II-induced hypertension, ST2 is crucial in promoting cardioprotective mechanisms. Abolishment of ST2 signalling in mice leads to marked hypertrophy following Ang II hypertension. Conversely, cardiac fibrosis, a common pathophysiological process in hypertension, may be inhibited by IL-33 in our hypertension model. Our results indicate a pleiotropic role of the IL-33/ST2 axis in hypertension.

Single-cell RNA sequencing (scRNA-Seq) data analysis performed in samples of heart transplant patients revealed that IL-33 is principally expressed by the vascular endothelial cells, fibromyocytes and fibroblasts in normal and diseased vessels. Additionally, in the human hypertensive mammary arteries, the expression of IL-33 was localised in endothelial cells. The OLINK dataset in the UK Biobank cohort depicted a positive correlation between plasma ST2 and BP parameters. We, therefore, suggest that sST2 (soluble ST2) could represent a potential risk factor for hypertension and may represent a promising novel marker for the prediction of hypertension and associated cardiovascular damage.

Overall, this study suggests a pleiotropic role for the IL-33/ST2 axis in hypertension. The actions of IL-33 are potentially mediated through non-immune cells, including vascular smooth muscle cells and ST2 through immune cells. This work provides insight into the functional effects of IL-33 and ST2 in hypertension and forms the basis for further work on uncovering its potential as a therapeutic target in hypertension and other vascular disease.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Subjects: Q Science > QR Microbiology > QR180 Immunology
R Medicine > R Medicine (General)
Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Funder's Name: European Research Council (ERC)
Supervisor's Name: Guzik, Professor Tomasz and Maffia, Professor Pasquale
Date of Award: 2024
Depositing User: Theses Team
Unique ID: glathesis:2024-84188
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 03 Apr 2024 08:50
Last Modified: 03 Apr 2024 08:55
Thesis DOI: 10.5525/gla.thesis.84188
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