Lead Researchers: Prof Helge Rasmussen, Dr Chia-Chi Liu, Dr Elisha Hamilton
Maternal and neonatal mortality is a global public health problem, that leads to about 295,000 maternal deaths every year during pregnancy and childbirth, and 5.2 million deaths among children under five years of age. Pre-eclampsia remains one of the few fatal complications of pregnancy in industrialised countries today. In contrast to other diseases, the field has not progressed significantly despite the massive global burden it represents.
Professor Rasmussen and his team have been looking at repurposing Beta3 Adrenergic receptor agonists, a drug already FDA-approved for the treatment of overactive bladders, as a treatment that could offer improved care of ‘high-risk’ pregnancies with pre-eclampsia and/or IUGR. It’s hoped that this will enhance future maternal cardiovascular health.
The team has discovered an abnormality that occurs on part of the Na+-K+ pump that is caused by ROS (reactive oxygen species), highly reactive molecules that can cause damage to cells and tissues, contributing to lots of diseases – including pre-eclampsia. They have established that when cells were exposed to low oxygen levels followed by reoxygenation (which is a change from low oxygen to normal oxygen levels), two important proteins involved in cell function, namely the β1 subunit of the Na+-K+ pump and eNOS, had a significant increase in glutathionylation, where they had a molecule called glutathione attached to them, which caused an impairment to their function. Additionally, the team observed that another protein called NADPH oxidase, which is responsible for generating ROS, also became more active under these conditions, indicating an increase in ROS formation.
Adding the β3AR agonist drug, CL, reduced the increase in glutathionylation of the β1 subunit of the Na+-K+ pump, as well as the activity of some important enzymes. This means that the β3AR agonist CL had a protective effect and prevented the excessive activation of these proteins.
Professor Rasmussen and his team have found that β3AR agonists are able to counteract the damage that occurs due to oxidative damage which holds promise for potential therapeutic interventions. By targeting and activating theβ3AR with drugs, the aim is to mitigate the effects of oxidative damage that are present in pre-eclampsia and potentially use this as a treatment – a hugely exciting discovery.