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.