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Title: The effects of the ω-6 polyunsaturated fatty acid dihomo-γ-linolenic acid on platelet function
Author: Menke, Laura
ISNI:       0000 0004 8508 1275
Awarding Body: Queen Mary University of London
Current Institution: Queen Mary, University of London
Date of Award: 2020
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Eicosanoids play an essential role in platelet function as they can both stimulate and inhibit platelet reactivity. Current anti-thrombotic therapies include aspirin that inhibits the enzyme COX-1 and thereby the production of arachidonic acid (AA)-derived, pro-aggregatory eicosanoids from platelets. Despite generally promising clinical outcomes, aspirin has limitations in efficacy and is associated with various side effects, highlighting the need for improved therapies. Eicosanoid synthesis can be altered by changes in substrate availability as well as by inhibition of pathway enzymes. For example, the omega-6 fatty acid dihomo-γ-linolenic acid (DGLA) can be utilized by platelets for the synthesis of anti-aggregatory eicosanoids, especially via pathways independent of COX-1, and can thus promote platelet inhibition. The objectives of this thesis were therefore to investigate the effects of DGLA on platelet reactivity and further examine the DGLA effects together with aspirin. In this study, I found that DGLA inhibits a variety of platelet functions, including platelet aggregation, adhesion, spreading and the surface expression of platelet activation markers. I further showed that DGLA inhibits α- and dense granule release and alters the platelet proteomic releasate profile, especially in the presence of aspirin. Pathway enrichment analysis predicted that addition of DGLA would further inhibit platelet-specific responses compared to aspirin alone, and might also influence inflammation and tissue repair, suggesting an exciting potential of DGLA to enhance therapeutic strategies for vascular diseases. Additionally, DGLA caused loss 8 in proteins linked to cytoskeletal rearrangement and initiated a unique physical phenotype in activated platelets similar to unstimulated platelets with curved elongations. Investigating the eicosanoid profile in response to DGLA, I found that DGLA did not alter the production of AA-derived eicosanoids, however, promoted the production of anti-aggregatory series-1 prostaglandins, 12-HETrE and the anti-inflammatory 15-HETrE and 8-HETrE. While aspirin inhibited AA-derived prostanoid production, it only minimally reduced DGLA-derived prostaglandin production, suggesting the involvement of still uncharacterised production pathways.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Barts and the London School of Medicine and Dentistry ; Blizard Institute