Institute of Anesthesiology, University Hospital, Zurich, Switzerland.
Cell Death Differ. 2013 Nov;20(11):1569-79. doi: 10.1038/cdd.2013.113. Epub 2013 Aug 30.
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.
细胞外血红蛋白 (Hb) 已被认为是镰状细胞病、疟疾和输血等溶血性疾病的发病诱因。在体内，许多游离 Hb 的不良影响可以通过 Hb 清除急性期蛋白触珠蛋白 (Hp) 来减弱。游离 Hb 可能引起的主要生理紊乱发生在心血管系统中，并且已经提出 Hb 触发的内皮氧化毒性是一种潜在的机制。这种毒性的分子机制以及 Hp 的保护作用尚不清楚。在这项研究中，我们在过氧化物应激下的内皮细胞系统中系统地研究了 Hb 毒性的结构、生化和细胞生物学性质。我们确定了两种主要的氧化 Hb 毒性机制，分别由珠蛋白降解产物和修饰的脂蛋白物种介导。这两种损伤途径引发不同和有区别的炎症和细胞毒性反应。Hp 提供了 Hb 的结构稳定性，并阻止了 Hb 与脂蛋白的氧化反应，从而对两种毒性途径提供了显著的保护。通过这些机制，Hp 在过氧化物应激期间将 Hb 的破坏性拟过氧化物反应转变为潜在的抗氧化功能。
