Vascular dysfunction importantly contributes to mortality and morbidity in various cardiac and
metabolic diseases. Among endogenous molecules regulating vascular tone is
adenosine, with the
adenosine A3 receptor (A3AR) exerting cardioprotective properties in
ischemia and reperfusion. However, overexpression of A3AR is suggested to result in vascular dysfunction and
inflammation. The leukocyte
enzyme myeloperoxidase (MPO) is an important modulator of vascular function with
nitric oxide-consuming and proinflammatory properties. Increased MPO plasma levels are observed in patients with cardiovascular disorders like
heart failure,
acute coronary syndromes, and arrhythmias. Given that vascular dysfunction and
inflammation are also hallmarks of diabetes, the role of MPO in
adenosine-dependent vasomotor function was investigated in a murine model of
diabetes mellitus. Wild-type (WT) and MPO-deficient (Mpo) mice were treated with
Streptozotocin (STZ), which induced an increase of MPO plasma levels in WT mice and led to enhanced aortic
superoxide generation as assessed by
dihydroethidium staining in STZ-treated WT mice as compared with controls. The vasoconstriction of aortic segments in response to the A3AR agonist Cl-
IB-MECA (2-Chloro-N6-(3-iodobenzyl)-N-methyl-5-carbamoyladenosine) as determined by isometric force measurements was augmented in diabetic WT as compared with diabetic Mpo mice. Moreover, A3AR
protein expression was enhanced in STZ-treated mice but was attenuated by
MPO deficiency. The current data reveal an MPO-mediated increase of vascular A3AR expression under diabetic conditions, which leads to enhanced vasoconstriction in response to A3AR agonists and discloses an additional mechanism of MPO-mediated vascular dysfunction.