Heme oxygenase-1 is a modulator of inflammation and vaso-occlusion in transgenic sickle mice

Abstract

Transgenic sickle mice expressing β S hemoglobin have activated vascular endothelium that exhibits enhanced expression of NF-κB and adhesion molecules that promote vascular stasis in sickle, but not in normal, mice in response to hypoxia/reoxygenation. Sickle mice hemolyze rbcs in vivo as demonstrated by increased reticulocyte counts, plasma hemoglobin and bilirubin, and reduced plasma haptoglobin. The heme content is elevated in sickle organs, which promotes vascular inflammation and heme oxygenase-1 expression. Treatment of sickle mice with hemin further increases heme oxygenase-1 expression and inhibits hypoxia/reoxygenation-induced stasis, leukocyte-endothelium interactions, and NF-κB, VCAM-1, and ICAM-1 expression. Heme oxygenase inhibition by tin protoporphyrin exacerbates stasis in sickle mice. Furthermore, treatment of sickle mice with the heme oxygenase enzymatic product carbon monoxide or biliverdin inhibits stasis and NF-κB, VCAM-1, and ICAM-1 expression. Local administration of heme oxygenase-1 adenovirus to subcutaneous skin increases heme oxygenase-1 and inhibits hypoxia/reoxygenation-induced stasis in the skin of sickle mice. Heme oxygenase-1 plays a vital role in the inhibition of vaso-occlusion in transgenic sickle mice.

Altered levels of cytokines and inflammatory mediators in plasma and leukocytes of sickle cell anemia patients and effects of hydroxyurea therapy

“…This enzyme is induced at the transcriptional level by heme, hypoxia, and cytokines amongst other stimuli. HO-1 expression is elevated in the organs of transgenic sickle mice [46], and we found the gene expression of this enzyme to be induced significantly in the MC and neutrophils of our SCA patient population, as also reported in another population of SCD individuals [47], suggesting this to be one of the anti-inflammatory mechanisms used by the organism in SCA. Interestingly, HU therapy slightly, but not significantly, increased the expression of this enzyme in these inflammatory cells, indicating this to be one of the beneficial effects of HU therapy.…”

Genetic variants and cell-free hemoglobin processing in sickle cell nephropathy

“…64 Furthermore, increased expression of HMOX1 has been observed in a porcine proximal tubular cell line exposed to urine from a patient with paroxysmal nocturnal hemoglobinuria 52 and in the kidneys of sickle cell mice. 64,65 A protective role for Hmox1 is suggested by several 52,66 but not all 67 studies. The HMOX1 GT-tandem repeat polymorphism has been previously shown to correlate with Hmox1 activity.…”

Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins

“…In studies using a model of vascular stasis, induction or overexpression of HO-1 inhibited the vascular stasis induced by hypoxia. [67][68][69] Furthermore, infusion of hemoglobin or heme into sickle mice induced vascular stasis that could be inhibited by Hp or Hpx supplementation. 70 In the prooxidative environment of sickle cell anemia, Hb-Fe 2ϩ may react with NO or other oxidants to generate Hb-Fe 3ϩ , from which hemin is released.…”