Heparin, Myeloperoxidase, and Atherosclerosis

Myeloperoxidase (MPO) is a heme-containing, cationic, and glycosylated protein abundantly prestored in azurophilic granules of polymorphonuclear leukocytes (PMNLs) and, in small quantities, in monocytes and macrophages (1). On degranulation of PMNLs, the enzyme exerts microbicidal effects, accumulates in blood vessels and forms potent oxidants that are involved in the damage of various biological molecules and tissue degradation, and are convincingly implicated in atherosclerosis, cardiovascular disease, diabetic vascular complications, kidney disease, and other disorders (1). Recently, it was shown that transgenic mice expressing the human MPO gene selectively in macrophages develop accelerated atherosclerosis (2). The conclusion of the study was that the macrophage-specific MPO might be a potential aim for new antiatherosclerotic drugs. Hence, we wish to recall some MPO-related and protective effects of an old drug, heparin, that are exerted on PMNLs and the blood vessels as an ultimate victim of atherosclerosis. As reviewed by Elsayed and Becker (3), heparin is a pluripotential anti-inflammatory agent. Relevant in vitro studies showed that (among other effects) heparin is capable of dose-dependently decreasing the percentage of phagocytying PMNLs and suppressing their respiratory burst (which diminishes the release of MPO from the intracellular azurophilic granules) as well as of specifically inhibiting adhesion of human PMNLs to cultured endothelial cells. The latter effect was evidenced for unfractionated heparin (UFH), lowmolecular-weight heparin (LMWH) dalteparin, and, interestingly, for a selectively desulfated derivative of heparin lacking anticoagulant activity (3). Regarding the vascular wall, Baldus and colleagues (4) found that MPO was accumulated in the subendothelial matrix not only via direct PMNLs degranulation on the endothelial surface and diapedesis but also due to transcytosis of the circulating MPO. In these experiments, pretreatment of both cultured endothelial cells and rat aortic tissues with UFH or LMWH enoxaparin reduced their MPO-bound activity and MPO protein content by almost 10 times, which markedly prevented nitrotyrosine formation indicative of vessel damage. In confirmation, Daphna and colleagues (5) showed that UFH could effectively displace purified MPO from endothelial cells in vitro, which was associated with less destructive oxidation of other prebound proteins of the vessel wall. Clinical studies performed in patients undergoing maintenance hemodialysis therapy and receiving large doses of heparin three times a week for blood anticoagulation in the extracorporeal circuit provided further evidence supportive to the above experimental studies. The heparin-using hemodialysis procedures produced a rapid and profound increase in plasma MPO levels (6,7), which was due to the release of the injurious enzyme from its complexes with glycosaminoglycans present on the endothelial surface and within the extracellular matrix of the vessels. It is noteworthy that hemodialysis treatments anticoagulated with trisodium citrate completely abolished the MPO upregulation compared with the UFH procedures (6). Moreover, hemodialyses employing nafamostate mesylate instead of UFH or LMMH resulted in no overdialytic increase in plasma MPO levels (7). Thus it seems that new MPO-oriented therapeutic perspectives arise from the “old, good” heparin. The subject is even more promising because heparin derivatives devoid of anticoagulant properties are under development (3) and are likely to be useful in the prevention and/or treatment of atherosclerosis. As recently shown, plasma MPO levels markedly increase following unfractionated heparin administration in patients undergoing coronary angiography (8). The MPO increase closely correlates with improved endothelial nitric oxide bioavailability, as evidenced by significantly enhanced flow mediated dilation and acetylcholine-induced changes in