Atherogenesis May Involve the Prooxidant and Proinflammatory Effects of Ferryl Hemoglobin

Abstract

Oxidized cell-free hemoglobin (Hb), including covalently cross-linked Hb multimers, is present in advanced atherosclerotic lesions. Oxidation of Hb produces methemoglobin (Fe3+) and ferryl hemoglobin (Fe4+ = O2−). Ferryl iron is unstable and can return to the Fe3+ state by reacting with specific amino acids of the globin chains. In these reactions globin radicals are produced followed by termination reactions yielding covalently cross-linked Hb multimers. Despite the evanescent nature of the ferryl state, herein we refer to this oxidized Hb as “ferryl Hb.” Our aim in this work was to study formation and biological effects of ferrylHb. We demonstrate that ferrylHb, like metHb, can release its heme group, leading to sensitization of endothelial cells (ECs) to oxidant-mediated killing and to oxidation of low-density lipoprotein (LDL). Furthermore, we observed that both oxidized LDL and lipids derived from human atherosclerotic lesions trigger Hb oxidation and subsequent production of covalently cross-linked ferrylHb multimers. Previously we showed that ferrylHb disrupts EC monolayer integrity and induces expression of inflammatory cell adhesion molecules. Here we show that when exposed to ferrylHb, EC monolayers exhibit increased permeability and enhanced monocyte adhesion. Taken together, interactions between cell-free Hb and atheroma lipids engage in a vicious cycle, amplifying oxidation of plaque lipids and Hb. These processes trigger EC activation and cytotoxicity.

Cell-free hemoglobin promotes primary graft dysfunction through oxidative lung endothelial injury

“…While other studies have reported associations between circulating CFH and alterations in endothelial function in models of atherosclerosis, malaria, and sickle cell disease (38)(39)(40), there have been few prior studies of the direct effects of CFH on microvascular endothelial permeability (41). Oxidized CFH, which is present in atherosclerotic plaques, results in intercellular gap formation and increased permeability in cultured endothelial cell monolayers (42,43). Hypoxia-responsive genes including HIF have also been implicated in hemoprotein-induced endothelial permeability in dermal microvascular endothelial cells (41).…”

Heme on innate immunity and inflammation

“…ferrylHb undergoes intermolecular cross-linking of its globin chains forming aggregates, which induces the expression of adhesion molecules in vascular endothelial cells that support the recruitment of macrophages into the vessel wall (Silva et al, 2009; Potor et al, 2013). Similarly to heme, ferrylHb activates endothelial cells through NFκB activation (Silva et al, 2009).…”

Chronic morbidities of premature newborns

“…Leírtuk azt is, hogy a sejtek a reaktív oxigéngyökökkel szemben egy indukálható, endogén védelmi mechanizmussal rendelkeznek, ez a transzkripciós szinten regulálható hemoxigenáz-1 enzim (HO-1) és a poszttranszkripciós szinten szabályozott ferritinrendszer [25,26,27,28,29]. A rendszer bilirubin mediálta antioxidáns potenciálján túl befolyással bír a sejtek, szövetek differenciálódására a ferritinnek a vasanyagcserére gyakorolt hatása által, sőt a korábban melléktermékként számon tartott szén-monoxidnak is van szabályzó funkciója, antitrombotikus, antiapoptotikus és antiinfl ammatiós sajátosságú [30,31].…”