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  • Importantly MPO is not only a marker


    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]. JLK 6 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 JLK 6 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]. Given that ETRB expression is regulated in a redox sensitive fashion [34], [35], we tested whether MPO also affects its expression and modulates its vasoconstrictive response. Here we provide evidence that upon binding to endothelial and smooth muscle cells, MPO increased expression of ETRB via classical MAP kinase cascades, which translated into augmented vasoconstriction.
    Materials and methods
    Discussion Myeloperoxidase (MPO) is released by activation of PMN into the vessel and binds to the endothelium prior to transcytosis into the subendothelial space [11]. By directly depleting the bioavailability of nitric oxide, interfering with NO⋅-synthase (eNOS) substrates and activity [12], [15], [18], [19], [20] MPO has shown to attenuate vasodilatation. The fact however, that MPO also affects vasoconstriction by interfering with the endothelin pathway importantly adds to the vasoactive properties of this enzyme. ETRB expression is sensitive to various pathophysiological states of disease and closely linked to vascular function [29], [30], [32], [33], [35], [42]. For example, it was demonstrated that ETRB expression on smooth muscle cells (SMC) is increased in atherosclerotic plaques and surrounding neointima [29] as well as in coronary arteries from human atherosclerotic hearts [30]. Stenman et al. [42] reported increased ETRB-dependent vasoconstriction of rat middle cerebral arteries after ischemia and reperfusion due to induction of SMC ETRB. Furthermore, induction of ETRB and ETRB-dependent constriction was present in vessels from hypertensive patients and rats [32], [33].