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Title: COX-2 and the vascular system : interactions with endothelial pathways and the eNOS system
Author: Al-Yamani, Malak
ISNI:       0000 0004 7969 7938
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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Endothelial cells release protective hormones such as prostacyclin and nitric oxide involving the enzyme pathways of cyclooxygenase and nitric oxide synthase (NOS). Both prostacyclin and nitric oxide act to oppose the effects of thromboxane A2 released following the actions also of cyclooxygenase by platelets. Cyclooxygenase (cyclooxygenase-2) is also present in inflammation and is the therapeutic target for the nonsteroidal anti-inflammatory group of drugs (NSAIDs). NSAIDs are among the most popular in the world. But NSAIDs also have side effects in the gut, this is why selective cyclooxygenase-2 types of NSAID were introduced. However, now after their introduction, there is an important concern regarding the cardiovascular side effects caused by all NSAIDs that work by blocking cyclooxygenase-2. My PhD thesis has used a number of techniques to show that the constitutive isoform (cyclooxygenase-1) drives prostacyclin in blood vessels and that in the kidney knocking out cyclooxygenase-2 results in changes in genes and proteins that regulate the methylarginines ADMA and LNMMA which are NOS inhibitors. I show that in cyclooxygenase-2 knock out mice ADMA and LNMMA are increased and that eNOS responses are reduced and that the effect is reversed by the substrate L-arginine. This work suggests that ADMA could explain why NSAIDs that work by blocking cyclooxygenase-2 affects endothelial responses in an indirect way. The data also suggests that ADMA could be a biomarker and that for some people L-arginine supplements might be protective. By using a mathematical model that I devised myself I also showed that cyclooxygenase-2 knock out causes morphological changes in the endothelium that suggest that in that region the enzyme might be pro-inflammatory and that for this observation a relationship with eNOS does not seem to be involved.
Supervisor: Mitchell, Jane ; Paul-Clark, Mark Sponsor: Jāmiʻat al-Malik Saʻūd
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral