title: Hepatic Overexpression of Hemopexin Inhibits Inflammation and Vascular Stasis in Murine Models of Sickle Cell Disease.
abstract: Sickle cell disease (SCD) patients have low serum hemopexin (Hpx) levels due to chronic hemolysis. We hypothesize that in SCD mice, hepatic overexpression of hemopexin will scavenge the proximal mediator of vascular activation, heme, and will inhibit inflammation and microvascular stasis. To examine the protective role of Hpx in SCD, we transplanted bone marrow from NY1DD SCD mice into Hpx™/™or Hpx+/+C57BL/6 mice. Dorsal skin fold chambers were implanted in week 13 post-transplant and microvascular stasis (% non-flowing venules) evaluated in response to heme infusion. Hpx™/™sickle mice had significantly greater microvascular stasis in response to heme infusion than Hpx+/+sickle mice (p<0.05), demonstrating the protective effect of Hpx in SCD. We utilized Sleeping Beauty (SB) transposon-mediated gene transfer to overexpress wild-type rat Hpx (wt-Hpx) in NY1DD and Townes-SS SCD mice. Control SCD mice were treated with lactated Ringer's solution (LRS) or a luciferase (Luc) plasmid. Plasma and hepatic Hpx were significantly increased compared to LRS and Luc controls. Microvascular stasis in response to heme infusion in NY1DD and Townes-SS mice overexpressing wt-Hpx had significantly less stasis than controls (p<0.05). Wt-Hpx overexpression markedly increased hepatic nuclear Nrf2 expression, HO-1 activity and protein, the heme-Hpx binding protein and scavenger receptor, CD91/LRP1 and decreased NF-κB activation. Two missense (ms)-Hpx SB-constructs that bound neither heme nor the Hpx receptor, CD91/LRP1, did not prevent heme-induced stasis. In conclusion, increasing Hpx levels in transgenic sickle mice via gene transfer activates the Nrf2/HO-1 anti-oxidant axis and ameliorates inflammation and vaso-occlusion.
authors.affiliation: Division of Hematology, Oncology and Transplantation, Department of Medicine, 420 Delaware St SE, MMC 480, University of Minnesota, Minneapolis, Minnesota, USA.|Vascular Biology Center, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Vercellotti
authors.affiliation: Division of Hematology, Oncology and Transplantation, Department of Medicine, 420 Delaware St SE, MMC 480, University of Minnesota, Minneapolis, Minnesota, USA.|Vascular Biology Center, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Division of Hematology, Oncology and Transplantation, Department of Medicine, 420 Delaware St SE, MMC 480, University of Minnesota, Minneapolis, Minnesota, USA.|Vascular Biology Center, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Nguyen
authors.affiliation: Division of Hematology, Oncology and Transplantation, Department of Medicine, 420 Delaware St SE, MMC 480, University of Minnesota, Minneapolis, Minnesota, USA.|Vascular Biology Center, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Fuad
authors.initials: F
authors.lastname: Abdulla
authors.affiliation: Division of Hematology, Oncology and Transplantation, Department of Medicine, 420 Delaware St SE, MMC 480, University of Minnesota, Minneapolis, Minnesota, USA.|Vascular Biology Center, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Chen
authors.affiliation: Division of Hematology, Oncology and Transplantation, Department of Medicine, 420 Delaware St SE, MMC 480, University of Minnesota, Minneapolis, Minnesota, USA.|Vascular Biology Center, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Phong
authors.initials: P
authors.lastname: Nguyen
authors.affiliation: Division of Hematology, Oncology and Transplantation, Department of Medicine, 420 Delaware St SE, MMC 480, University of Minnesota, Minneapolis, Minnesota, USA.|Vascular Biology Center, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Nowotny
authors.affiliation: Division of Gastroenterology, Department of Medicine, and Department of Genetics, Cell Biology and Development, 420 Delaware St SE, MMC 36, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Steer
authors.affiliation: Division of Molecular Biology and Biochemistry, School of Biological Sciences, University of Missouri-Kansas City, Kansas City, Missouri, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Smith
authors.affiliation: Division of Hematology, Oncology and Transplantation, Department of Medicine, 420 Delaware St SE, MMC 480, University of Minnesota, Minneapolis, Minnesota, USA.|Vascular Biology Center, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Belcher
keywords: endothelial cell; gene transfer/gene therapy; hematology; inflammation; ischemia