[HTML][HTML] Mechanisms of haptoglobin protection against hemoglobin peroxidation triggered endothelial damage

CA Schaer, JW Deuel, AG Bittermann… - Cell Death & …, 2013 - nature.com
CA Schaer, JW Deuel, AG Bittermann, IG Rubio, G Schoedon, DR Spahn, RA Wepf
Cell Death & Differentiation, 2013nature.com
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 …
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.
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