Targeted therapies against cardiovascular disease

CVD is the leading cause of death and disability in Europe. Current treatment approaches are purely symptomatic since the mechanisms of CVD are not well understood. Accumulating evidence indicates that the increased occurrence of oxygen radicals known as oxidative stress relates to CVD.

The EU-funded RADICAL PHARMACOLOGY (Free radical pharmacology: Generators, targets and therapeutic implications) project set out to investigate further the association between CVD and oxidative stress. In particular, researchers were interested in identifying targetable sources of radical signals that are relevant for CVD and establish strategies for reversing the molecular damage. The long-term goal was to develop new markers for diagnosis of CVD in humans and design mechanism-based treatments.

Results identified the NADPH oxidases NOX4 and NOX5 as novel, mechanism-based therapeutic targets for ischaemic stroke and diabetic nephropathy. These enzymes generate free radicals and are responsible for oxidative damage. Similarly, NOX1 proved to be a target in diabetic atherosclerosis and retinopathy. A number of drugs exhibited substantial inhibition of these enzymes and were forwarded for clinical development.

In addition, the consortium discovered that the receptor for nitric oxide was downregulated in stroke cases and drug-mediated activation exhibited therapeutic efficacy. This new class of molecules also went into clinical development.

Scientists generated evidence towards a protective association of high nitric oxide levels and potentiation with ROS. This suggested possible combinatorial therapies for targeting oxidative stress as an intervention against CVD.

Collectively, the RADICAL PHARMACOLOGY findings enhanced our understanding of the role of oxidative stress in cardiovascular physiology and function. Importantly, they provided novel therapeutic targets against CVD.