br Introduction Recruitment and activation of neutrophils

Introduction Recruitment and activation of neutrophils (PMN) [1] are characterized by liberation of intracellular granules. Myeloperoxidase (MPO), stored in primary granules of PMN, is among the principal enzymes released. Of note, increased levels of circulating MPO can be also detected in patients with coronary artery disease, unstable self-flagellation and acute myocardial infarction [2], [3], [4], [5] and indicate adverse outcome [6], [7]. Also, MPO plasma levels are predictive of outcome in patients presenting in the early phase after onset of chest pain [8], [9] and correlate with an impaired left-ventricular function [10]. Importantly, MPO is not only a marker of cardiovascular disease but also emerges as a critical mediator of vascular inflammatory disease: Liberated MPO binds to the endothelium in a leukocyte-independent manner, is subsequently taken up by the endothelium and transcytoses and accumulates in the subendothelial space [11], [12], [13], [14]. Here, MPO demonstrated to critically regulate vasomotor properties: MPO oxidizes nitric oxide (NO⋅) directly as well as indirectly via oxidation of NO⋅-derived small radical intermediates [12], [15], [16], [17]. It further affects NO⋅ bioavailability by uncoupling endothelial NO⋅ synthase (eNOS) [18], oxidizing the eNOS substrate l-arginine and by increasing the bioavailability of endogenous NO⋅ synthase inhibitors [19], [20]. Endothelin-1 (ET-1), a 21-aa polypeptide mainly generated and secreted by vascular endothelial cells, is one of the most potent vasoconstrictors known to date. Additionally, it exerts mitogenic properties towards vascular smooth muscle cells, endothelial cells and tumor cells [21], [22], [23]. ET-1 acts via two receptor molecules: the endothelin receptors type A and B (ETRA and ETRB). In the vessel wall the constitutively expressed ETRA can be detected only on smooth muscle cells, whereas the inducible ETRB is expressed by smooth muscle cells as well as by endothelial cells. On endothelial cells ETRB mediates the ET-1-dependent vasodilation via stimulation of the release of vessel-relaxing substances like NO⋅ and prostacyclines. Additionally, endothelial ETRB is responsible for removal of ET-1 from the circulation by pulmonary clearance and endothelial re-uptake of ET-1. On smooth muscle cells, ETRB as well as ETRA leads to ET-1-dependent vasoconstriction [24], [25]. Most arteries from healthy humans or animals show little or no contractile response to ETRB-specific agonists due to only minor amounts of ETRB protein expressed on smooth muscle cells compared to ETRA [26], [27], [28]. However, induction of smooth muscle cell ETRB expression can be detected in patients and/or animal models with atherosclerosis [29], [30], ischemic heart disease [31], as well as hypertension [32], [33]. This increase can be mimicked by incubating the vessels under organ culture conditions for 1d in serum-free medium, an established model for induction of ETRB expression in vessels ex vivo thereby mimicking endothelial dysfunction [34], [35].