The role of phosphoinositide 3-kinases and Rac GTPases in vascular inflammation

Abstract

Phosphoinositide-3 kinases and Rac GTPases play important roles in a wide variety of cellular responses downstream of cell surface receptors. Although their activation and functions in cultured cells are well studied, their contributions to cellular processes in vivo, such as leukocyte accumulation at sites of acute and chronic inflammatory responses, are less well-characterised. Inflammatory oedema formation and leukocyte accumulation are initiated by changes to the endothelial cells lining blood vessels to combat injury and infection. Whilst the endothelial barrier remains tight under physiological conditions, it becomes dysfunctional in response to tissue injury, for example during heart failure. The inflammatory component of cardiovascular disease is associated with endothelial damage, resulting in leukocyte trafficking and oedema formation. This has direct implications on the endothelial monolayer in the vasculature, disrupting cell-cell junctional proteins, increasing microvascular permeability, and resulting in a positive-feedback loop of inflammatory events. However, few treatments for heart disease specifically target the endothelium. The PI3K and Rac GTPase pathway has been implicated in stimulating this response whereby inhibitors of these, have shown to attenuate this effect. Both PI3K and Rac GTPases have downstream roles in endothelial cells and the use of transgenic mouse models, and isoform-selective or non-selective inhibitors suggest that these pathways play a role in leukocyte recruitment to sites of inflammation. Thus, this pathway may present novel opportunities for PI3K and Rac GTPase inhibitors to be used as effective therapeutic treatments for cardiovascular-related inflammatory conditions.

Date of Award	1 Sept 2022
Original language	English
Awarding Institution	King's College London
Supervisor	Susan Brain (Supervisor) & Anne Ridley (Supervisor)