Myeloperoxidase deficiency preserves vasomotor function in humans

Published: EUROPEAN HEART JOURNAL 33, 1625-1634 Authors: Rudolph, TK., Wipper, S., Reiter, B., Rudolph, V., Coym, A., Detter, C., Lau, D., Klinke, A., Friedrichs, K., Rau, T., Pekarova, M., Russ, D., Knoll, K., Kolk, M., Schroeder, B., Wegscheider, K., Andresen, H., Schwedhelm, E., Boeger, R., Ehmke, H., Baldus, S. Year: 2012

Abstract

Observational studies have suggested a mechanistic link between the leucocyte-derived enzyme myeloperoxidase (MPO) and vasomotor function. Here, we tested whether MPO is systemically affecting vascular tone in humans. A total of 12 135 patients were screened for leucocyte peroxidase activity. We identified 15 individuals with low MPO expression and activity (MPOlow), who were matched with 30 participants exhibiting normal MPO protein content and activity (control). Nicotine-dependent activation of leucocytes caused attenuation of endothelial nitric oxide (NO) bioavailability in the control group (P 0.01), but not in MPOlow individuals (P 0.12); here the MPO burden of leucocytes correlated with the degree of vasomotor dysfunction (P 0.008). To directly test the vasoactive properties of freecirculating MPO, the enzyme was injected into the left atrium of anaesthetized, open-chest pigs. Myeloperoxidase plasma levels peaked within minutes and rapidly declined thereafter, reflecting vascular binding of MPO. Blood flow in the left anterior descending artery and the internal mammary artery (IMA) as well as myocardial perfusion decreased following MPO injection when compared with albumin-treated animals (P 0.001). Isolated IMA-rings from animals subjected to MPO revealed markedly diminished relaxation in response to acetylcholine (P 0.01) and nitroglycerine as opposed to controls (P 0.001). Myeloperoxidase elicits profound effects on vascular tone of conductance and resistance vessels in vivo. These findings not only call for revisiting the biological functions of leucocytes as systemic and mobile effectors of vascular tone, but also identify MPO as a critical systemic regulator of vasomotion in humans and thus a potential therapeutic target.