Determining the role of the ADMA-DDAH1 pathway in ischaemic stroke

Asymmetric dimethyl arginine (ADMA) is an endogenously produced inhibitor of nitric oxide (NO) synthesis and as such exerts significant effects on vascular homeostasis. ADMA is primarily metabolised by the dimethylarginine dimethylaminohydrolase (DDAH) enzymes, DDAH1 and DDAH2. Elevated ADMA levels are associated with stroke risk and worse stroke outcome, however, causal evidence is lacking.

The overarching aim of this proposal is to address this lack of understanding.

Our pilot experiments show that DDAH1 inhibition impairs eNOS-NO-regulated processes in cerebral arteries, and increases brain injury following ischaemic stroke.

Thus, in this project we will test whether elevated ADMA resulting from reduced DDAH1 activity worsens stroke outcome by perturbing eNOS-NO signaling.

We will examine the impact of elevated ADMA on cerebrovascular NO synthesis, vasodilatation, brain perfusion in vivo, and angiogenesis following ischaemia-reperfusion.

Furthermore, we will examine the effect of elevated ADMA levels on the extent of ischaemic brain injury and functional impairment; and determine whether pharmacological lowering of ADMA levels improves stroke outcomes.

This project will provide the first proof-of-concept data pertaining the impact of the ADMA-DDAH1 pathway on stroke outcome.

It may ultimately lead to novel DDAH1-focused therapeutic approaches, and provide justification for the future monitoring and stratification of at risk patients.