The red blood cell: Mediator of cardiovascular disease and novel target for treatments

Background and aimThe project is focused on the red blood cell (RBC) as a previously unknown mediator of endothelial dysfunction and cardiac injury in cardiovascular disease (CVD) as a result of reduced export of nitric oxide (NO) bioactivity and increased oxidative stress driven by increased RBC arginase activity.

Using a combination mechanistic and randomized clinical studies we will test the hypothesis that RBC dysfunction is a key factor that drives development of atherosclerotic CVD, and that targeting this dysfunction prevents and attenuates cardiovascular injury.

Specific aims are to:Determine RBC-induced cardiovascular injury in patients with CVDIdentify the molecular signaling driving RBC-induced cardiovascular injuryExplore the efficacy of inhibiting RBC dysfunction as a novel therapeutic strategy Work planThe ability of RBCs from healthy controls and patients with diabetes, dyslipidemia, and developed atherosclerotic CVD to induce endothelial and cardiac injury is determined.

Underlying signaling mechanisms with focus on arginase, NO formation and oxidative stress are identified.

Therapeutic interventions targeting RBCs to increase NO bioactivity by inorganic nitrate, soluble guanylyl cyclase stimulator and arginase inhibitor are investigated ex vivo and in clinical studies.

SignificanceThe project has the potential to identify a novel mechanism behind atherosclerotic CVD caused by RBCs, which may lead to new treatment strategies for these patients.