Abstract 14525: Myeloperoxidase Systemically Regulates Vascular Tone
Background — Observational clinical and ex-vivo studies have suggested a mechanistic link between the leukocyte derived enzyme myeloperoxidase (MPO) and endothelial nitric oxide (NO) bioavailability. However, whether MPO systemically affects vascular tone and modulates hemodynamics in-vivo remains elusive.
Methods and results — 12,135 patients were screened for leukocyte 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 enzyme activity (control). Nicotine-dependent activation of leukocytes caused attenuation of endothelial NO bioavailability — as assessed by flow-mediated dilation — in the control group (P<0.01), but not in MPOlow individuals (P=0.12). To directly test the vasoactive properties of free circulating MPO, the enzyme was injected into the left atrium of anesthetized, open chest pigs. MPO plasma levels peaked within minutes and rapidly declined thereafter, reflecting binding of MPO to the vessel wall. Blood flow in the left anterior descending artery (LAD) and the internal mammary artery (IMA) as well as myocardial perfusion assessed by fluorescent microspheres and fluorescent cardiac imaging decreased following MPO injection as compared to 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).
Conclusions — MPO elicits profound effects on vascular tone of conductance and resistance vessels in-vivo. These findings not only call for revisiting the biological functions of leukocytes 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.
- © 2010 by American Heart Association, Inc.