Mechanisms of haptoglobin protection against hemoglobin peroxidation triggered endothelial damage

Abstract

Extracellular hemoglobin (Hb) has been recognized as a disease trigger in hemolytic conditions such as sickle cell disease, malaria, and blood transfusion. In vivo, many of the adverse effects of free Hb can be attenuated by the Hb scavenger acute-phase protein haptoglobin (Hp). The primary physiologic disturbances that can be caused by free Hb are found within the cardiovascular system and Hb-triggered oxidative toxicity toward the endothelium has been promoted as a potential mechanism. The molecular mechanisms of this toxicity as well as of the protective activities of Hp are not yet clear. Within this study, we systematically investigated the structural, biochemical, and cell biologic nature of Hb toxicity in an endothelial cell system under peroxidative stress. We identified two principal mechanisms of oxidative Hb toxicity that are mediated by globin degradation products and by modified lipoprotein species, respectively. The two damage pathways trigger diverse and discriminative inflammatory and cytotoxic responses. Hp provides structural stabilization of Hb and shields Hb's oxidative reactions with lipoproteins, providing dramatic protection against both pathways of toxicity. By these mechanisms, Hp shifts Hb's destructive pseudo-peroxidative reaction to a potential anti-oxidative function during peroxidative stress.

Spin trapping combined with quantitative mass spectrometry defines free radical redistribution within the oxidized hemoglobin:haptoglobin complex

“…The reaction cycle of Hb with H 2 O 2 has become an archetypical example of Hb's ability to catalyze oxidative modification of tissue protein and lipid components, as well at its own self-destruction [7][8][9][10][11][12]. In the absence of Hp these processes lead to cell damage and tissue injury [13].…”

Iron Supplementation Alters Heme and Heme Oxygenase 1 (HO-1) Levels In Pregnant Women in Ghana

“…This damaging effect is countered by the upregulation of HO-1 in the endothelium thereby alleviating and preventing vasoocclusion and the subsequent vascular inflammation frequently seen in SCD patients [40]. Other heme scavenging systems that are available in mammals to avert extracellular heme toxicity besides the Heme Oxygenase (HO) system include Haptoglobin (Hp) [41,42] and Hemopexin (Hx) [37] and albumin [31]. These heme scavenging systems detoxify free heme by forming a non-toxic heme complex or by its degradation or by scavenging free redoxactive iron (ferritin) released after heme catabolism [31].…”

Dynamic interactions ofPlasmodiumspp. with vascular endothelium

“…104 In addition, the barrier disruptive effects of heme could be mediated by NLRP3, 105 TLR4 106 or other MyD88 signaling pathways. 107 Heme induced inflammatory effects can be inhibited by hemoglobin-and heme-binding proteins such as haptoglobin 108 and hemopexin, 109 or detoxification of hemoglobin breakdown products by nitric oxide, 110 heme oxygenase-1 or carbon monoxide which converts toxic methemoglobin to carboxyhemoglobin. 111 …”