Oxidative stress and platelet hyperactivity: the role of NADPH oxidases in haemostasis regulation in health and diabetes.

Platelets are circulating blood cells that help to arrest of bleeding (i.e. haemostasis) and promote the repair of blood vessels following injury.

In type 2 diabetes mellitus (T2DM), platelets are hyperactive and their uncontrolled activation leads to the unwanted occlusion of blood vessels (i.e. thrombosis).

Thrombosis is the main cause of mortality for T2DM patients, who display significantly higher risk of cardiovascular disease than the rest of the population.

Currently, 70% of T2DM patients succumb to cardiovascular diseases.I have been working on pro-oxidant enzymes called NADPH oxidases (NOXs), which are responsible for oxidative stress and activation of platelets.

I have shown that the enzymatic activity of NOXs generates oxidant molecules (i.e. free radicals), which in turn are responsible for platelet activation.

In preparation to this application, I have generated data showing that platelets from T2DM patients contain higher levels of the NOX1 isoform.

This enzyme is responsible for oxidative stress and hyperactivity of platelets from T2DM platelets compared to healthy controls.

In this project, I aim to understand the molecular mechanisms underlying platelet regulation by NOXs and the contribution of NOX1 to platelet hyperactivity in T2DM. I will use human blood from T2DM patients and murine models of T2DM.

In addition to clarifying the role of NOX1 in the vascular complications of T2DM, I will test whether NOX1 inhibitors synthesised in my laboratory can protect the health of the vascular system in this disease.Taken together, this project will markedly advance our understanding of how platelets are regulated and will generate novel information on the link between cardiovascular risk and T2DM, which may result in a substantial improvement of the clinical management of this disease.