Molecular Biotechnology Center and Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
Circulation. 2013 Mar 26;127(12):1317-29. doi: 10.1161/CIRCULATIONAHA.112.130179. Epub 2013 Feb 27.
Hemolytic diseases are characterized by enhanced intravascular hemolysis resulting in heme-catalyzed reactive oxygen species generation, which leads to endothelial dysfunction and oxidative damage. Hemopexin (Hx) is a plasma heme scavenger able to prevent endothelial damage and tissue congestion in a model of heme overload. Here, we tested whether Hx could be used as a therapeutic tool to counteract heme toxic effects on the cardiovascular system in hemolytic diseases.
By using a model of heme overload in Hx-null mice, we demonstrated that heme excess in plasma, if not bound to Hx, promoted the production of reactive oxygen species and the induction of adhesion molecules and caused the reduction of nitric oxide availability. Then, we used β-thalassemia and sickle cell disease mice as models of hemolytic diseases to evaluate the efficacy of an Hx-based therapy in the treatment of vascular dysfunction related to heme overload. Our data demonstrated that Hx prevented heme-iron loading in the cardiovascular system, thus limiting the production of reactive oxygen species, the induction of adhesion molecules, and the oxidative inactivation of nitric oxide synthase/nitric oxide, and promoted heme recovery and detoxification by the liver mainly through the induction of heme oxygenase activity. Moreover, we showed that in sickle cell disease mice, endothelial activation and oxidation were associated with increased blood pressure and altered cardiac function, and the administration of exogenous Hx was found to almost completely normalize these parameters.
Hemopexin treatment is a promising novel therapy to protect against heme-induced cardiovascular dysfunction in hemolytic disorders.
溶血性疾病的特征是血管内溶血增强，导致血红素催化的活性氧生成，从而导致内皮功能障碍和氧化损伤。血红素结合蛋白（Hx）是一种血浆血红素清除剂，能够在血红素过载模型中预防内皮损伤和组织充血。在这里，我们测试了 Hx 是否可以用作治疗工具，以抵消溶血性疾病中血红素对心血管系统的毒性作用。
通过使用 Hx 缺失小鼠的血红素过载模型，我们证明了如果血浆中的血红素未与 Hx 结合，会促进活性氧的产生和粘附分子的诱导，并导致一氧化氮的生成减少。然后，我们使用β-地中海贫血和镰状细胞病小鼠作为溶血性疾病的模型，评估基于 Hx 的治疗方法在治疗与血红素过载相关的血管功能障碍方面的疗效。我们的数据表明，Hx 可防止血红素-铁在心血管系统中的蓄积，从而限制活性氧的产生、粘附分子的诱导以及一氧化氮合酶/一氧化氮的氧化失活，并通过诱导血红素加氧酶活性促进血红素的回收和解毒。此外，我们表明在镰状细胞病小鼠中，内皮激活和氧化与血压升高和心脏功能改变有关，而外源性 Hx 的给药被发现几乎完全使这些参数正常化。
血红素结合蛋白治疗是一种有前途的新型疗法，可以预防溶血性疾病中血红素诱导的心血管功能障碍。
