Melatonin Can Mediate Its Vascular Protective Effect by Modulating Free Iron Level by Inhibiting Hypochlorous Acid–Mediated Hemoprotein Heme Destruction

To the Editor:

A recent interesting study by Rezzani et al in Hypertension¹ has shown that melatonin treatment can reduce blood pressure in spontaneously hypertensive rats. The authors attributed this role of melatonin to its capacity to function as an antioxidant, as well as a vasodilator, by increasing the availability of NO. In response to this article, van der Zwan et al² proposed that melatonin's blood pressure modulating effect is not only attributed to its capacity as a potential antioxidant but also through its ability to inhibit myeloperoxidase (MPO) activity in vascular tissue. In our opinion, both of these two proposed mechanisms seem to be valid, but melatonin's role in controlling vascular phenomena is not limited to these two functions. Our recent preliminary results have shown that melatonin can prevent hypochlorous acid (HOCl)–mediated heme destruction in hemoglobin and highlights a new mean by which melatonin can exhibit its protective effect. Therefore, we propose that melatonin can exert the vasoprotective effect by modulating the level of free iron.

Recently, we have shown that melatonin can act as an effective inhibitor of MPO by forming an inactive melatonin-MPO-chloride complex and by accelerating the MPO compound II (MPO-Fe[IV]=O complex) formation and its decay to ferric MPO.³ In biological systems, MPO generates a potent oxidant, HOCl, which plays a protective role in innate immune response.⁴ However, under a number of pathological conditions, such as inflammatory diseases, atherosclerosis, pulmonary fibrosis, and cancer, HOCl is implicated in damaging the host tissue by the same mechanism used to destroy invading pathogens. Under these pathological conditions, there have been reports of significant catalytically active free iron accumulation.⁵ Free iron can damage blood vessels and produce vasodilation with increased vascular permeability, leading to hypotension and metabolic acidosis. The source of this iron is still unclear, but it is thought to be hemoglobin released from damaged red blood cells at sites of vascular turbulence or in hemorrhagic atheromatous plaques. We also believe that there is a mechanistic link between high HOCl and higher free iron levels. In a series of recent studies (articles under review) with purified proteins and isolated human red blood cells, we have shown that HOCl can mediate destruction of the heme moiety of hemoproteins, such as hemoglobin, lactoperoxidase, and MPO, to liberate free iron. HOCl degrades their heme moiety through a mechanism that involves sequential formation and degradation of ferryl peroxidase-like intermediates, compounds I and II. Because of melatonin's ability to destabilize these intermediates and scavenge HOCI, we hypothesized that melatonin can prevent hemoprotein heme destruction mediated by HOCl, because this process also involves the formation and destruction of peroxidase-like intermediates. Indeed, our preliminary results show that incubation of hemoglobin, MPO, and lactoperoxidase with melatonin, before HOCl treatment, prevents HOCl-mediated heme destruction and free iron release.

In summary we propose that, in addition to acting as an antioxidant and as an inhibitor for MPO, melatonin can also exert its protective effect by inhibiting HOCl-mediated heme destruction of hemoproteins and subsequent free iron release.

• © 2011 American Heart Association, Inc.