The role of inflammatory cytokines in endothelial dysfunction in hypertension

Sharma, Malvika (2024) The role of inflammatory cytokines in endothelial dysfunction in hypertension. PhD thesis, University of Glasgow.

Abstract

Hypertension is a pervasive cardiovascular disorder characterized by increased blood pressure levels. It is a global cause of morbidity and mortality and poses a heightened risk of serious cardiovascular complications. Although the role of kidney, vasculature, heart, and brain has been defined before, recent research has illuminated the pivotal role of immune mechanisms and inflammation in the development and progression of hypertension.

To delve into the intricate play of immune mechanisms in the development of hypertension, this thesis aims to identify the role of inflammatory cytokines in endothelial dysfunction in hypertension. Through a multifaceted approach, we pursued three primary aims of identifying association between inflammatory cytokines and incident hypertension in patient populations, assessing their direct vascular effects in mouse blood vessels and probing potential mechanisms of endothelial dysfunction.

To identify inflammatory cytokines potentially contributing to the incidence of hypertension, we ran systematic searches in Medline, Embase, Web of Science and Cochrane CENTRAL. After screening for inclusion and exclusion criteria, we performed meta-analysis of the relationships between the levels of identified cytokines from six records and incident hypertension. We have then undertaken mechanistic studies of the endothelium dependent and independent effects of selected cytokines on vasomotor functions in mouse aortas. Thoracic aortas from 3-month old C57BL6/J mice were treated with selected cytokine concentrations overnight and endothelium dependent and independent vasoconstriction and relaxation impairment was observed. We further selected two cytokines to study the potential mechanism of endothelial dysfunction by looking at eNOS and ERK phosphorylation in human aortic endothelial cells. The cells were treated with varying cytokine concentrations for different time periods and the differences in phosphorylation were observed in the cell homogenate using western blotting.

Through our systematic searches we selected fifteen records after screening and identified IL 6, IL-1β, TNF-α, IL-17a, and IFN-γ among other cytokines and metaanalysed data available from six records. We found that IL-6 is significantly associated with the risk of developing hypertension in crude models with high heterogeneity. In organ bath studies significant impairment was observed in vessels treated with selected cytokines. Endothelium-dependent relaxation observed using acetylcholine was significantly altered by IL-1β (1 ng/ml) after pre constricting the vessels with phenylephrine and serotonin (P<0.001 and P=0.04, respectively). Similar alteration of vasorelaxations was observed with IFN-γ (10 ng/ml) after constricting the vessels with phenylephrine (P=0.0099) and with IL-6 (5 ng/ml) after constricting the vessels with serotonin (P=0.014). Furthermore, western blot results demonstrated differences in eNOS and ERK phosphorylation.

We found that IL-6 is positively associated with incidence of hypertension, but this association weakens with adjusting for BMI implying a relationship between inflammation and adiposity linked hypertension. Significant impairment of endothelial function induced by IL-1β, IFN-γ and IL-6 suggests a direct link between endothelial dysfunction and inflammation. Further studies are needed to substantiate the results in identifying the mechanisms of inflammatory cytokines in endothelial dysfunction and understand their significance for patho-mechanisms of hypertension.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: Q Science > QH Natural history > QH345 Biochemistry; R Medicine > R Medicine (General)
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Supervisor's Name: Czesnikiewicz-Guzik, Dr. Marta
• Date of Award: 2024
• Depositing User: Theses Team
• Unique ID: glathesis:2024-84205
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 08 Apr 2024 12:42
• Last Modified: 08 Apr 2024 12:44
• Thesis DOI: 10.5525/gla.thesis.84205
• URI: https://theses.gla.ac.uk/id/eprint/84205

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