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Title: Stretch-activated channels in heart valve cells
Author: Alshammari, Hessah Farhan A.
ISNI:       0000 0004 8499 5040
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2019
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The aortic valve is a sophisticated structure that performs complex functions to preserve the unidirectional flow of blood and maintenance of myocardial function. Valve endothelial cells (VECs) cover the two surfaces of aortic valve cusps in a continuous layer consisting of the endocardium and the sinus wall endothelium. Valve interstitial cells (VICs) are a heterogeneous and dynamic population of cells that form the body of valve cusps and are located within the extracellular matrix. VECs experience continuous and different mechanical forces in both side and VICs are experience continuous and varying mechanical forces, including stretch. These mechanical forces are translated to the cells via electrochemical or biochemical signals through mechanotransduction pathways, which may include stretch-activated ion channels (SACs) which are membrane proteins capable of responding to mechanical force and activate intracellular signalling pathways that mediate the functional response of the cells. The overall aim of this study was to investigate SACs presence and their functional roles in VECs and VICs. The presence of stretch-activated ion channels was studied electrophysiologically and biochemically in VECs from each side of the valve and different phenotypes of VICs. The role of SAC on alignment of and proliferation VECs, migration and collagen production in VICs were assessed. Stretch-activated ion channels receptors including (KCNK2, KCNJ8, TRPM4, TRPV4 and TRPC6) were present in VECs and VICs. SACs have the same channel activity in VECs from aortic and ventricular sides, but the expression level of some SACs are significantly more in VECs isolated from the ventricular side. Additionally, functional roles of SACs in VECs was demonstrated where blocking of SACs significantly reduced VECs alignment under shear stress. SACs activity and expression varied in VICs of a fibroblast, myofibroblast and osteoblast phenotype, which correlated with changes in fibroblast and osteoblast markers. SACs blockers significantly reduced migration and collagen production of VICs in response to mechanical stretch. Also, SACs activators regulated VICs proliferation in static condition. In conclusion, SACs are present in VECs and VICs and have regulatory roles in some mechanically-mediated cells responses or function. This study shows a role for SACs in the mechanobiology of valve cells, and information provides a new insight towards understanding valve cell function in health and disease.
Supervisor: Chester, Adrian ; Kohl, Peter ; Latif, Najma Sponsor: Saudi Arabia Culture Bureau
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral