Heme oxygenase-1 is a modulator of inflammation and vaso-occlusion in transgenic sickle mice.
Transgenic sickle mice expressing betaS hemoglobin have activated vascular endothelium that exhibits enhanced expression of NF-kappaB 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-kappaB, 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-kappaB, 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.
Division of Hematology, Oncology, and Transplantation, Department of Medicine and Vascular Biology Center, University of Minnesota, Minneapolis, Minnesota 55455, USA. belcher@umn.edu
John D
JD
Belcher
Hemachandra
H
Mahaseth
Thomas E
TE
Welch
Leo E
LE
Otterbein
Robert P
RP
Hebbel
Gregory M
GM
Vercellotti
D000755:Anemia, Sickle Cell / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D006427:Hemin / Q000502:physiology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009928:Organ Specificity; D011524:Protoporphyrins / Q000494:pharmacology; D015854:Up-Regulation / Q000502:physiology; D014661:Vasoconstriction / Q000235:genetics
D018836:Inflammation Mediators; D008665:Metalloporphyrins; D011524:Protoporphyrins; D006427:Hemin; C032628:tin protoporphyrin IX; D051547:Heme Oxygenase-1