Myeloperoxidase deficiency preserves vasomotor function in humans

Abstract

AimsObservational 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.Methods and resultsA 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 free circulating 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).ConclusionMyeloperoxidase 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.

Protein Carbamylation Predicts Mortality in ESRD

“…17,29,30,36,37 MPO, an abundant granulocyte protein, is a known mediator of vascular inflammation and plaque vulnerability and has been mechanistically linked to almost all stages of CVD, including culprit lesions (i.e., at sites of atherosclerotic plaque rupture and intracoronary thrombus). 15,16,[38][39][40][41][42][43][44] MPO has prognostic ability to help risk-stratify these same MHD patients, 37 and thiocyanate, a preferred substrate for MPO and obligate cosubstrate with hydrogen peroxide in MPO-catalyzed protein carbamylation, is elevated in patients undergoing hemodialysis. 13,45 However, MPO mass concentrations in the present cohort had a very weak correlation with PBHCit (Table 2), and its inclusion in multilogistic regression analyses failed to attenuate the prognostic utility of PBHCit (Table 3).…”

Effects of age on noninvasive assessments of vascular function in nonhuman primates: implications for translational drug discovery

“…FMD was recorded at 5 min of vehicle infusion, and at 15 min of nicotine infusion (while the nicotine infusion was constantly maintained), and the study was completed within 35 min. The nicotine dose used was calculated to approximate the predicted blood nicotine concentration (40 nM) of a human study in which chewing nicotine gum reduced FMD [26,27]. …”

Myeloperoxidase, paraoxonase-1, and HDL form a functional ternary complex

“…Myeloperoxidase (MPO) is a leukocyte-derived heme protein that, like PON1, both binds to HDL and is mechanistically linked to oxidant stress and atherosclerosis (23)(24)(25)(26)(27). While typically found at very low levels within the plasma of healthy individuals, substantially elevated levels may be observed in the plasma or serum of those with acute coronary syndromes (ACS) and at risk for major adverse cardiac events (28).…”