title: Paradoxical enhancement of oxidative cell injury by overexpression of heme oxygenase-1 in an anchorage-dependent cell ECV304.
abstract: There has been increasing evidence suggesting the potent anti-inflammatory roles of heme oxygenase-1 (HO-1) in protecting renal tubular epithelial cells, vascular endothelial cells, and circulating monocytes. Based on these findings, novel therapeutic interventions have been proposed to control the expression of endothelial HO-1 levels to ameliorate various vascular diseases. We evaluated the effect of HO-1 gene transfer into an anchorage-dependent cell, ECV304. Effect of HO-1 production on the cell injury induced by hydrogen peroxide was evaluated after hemin stimulation and after HO-1 gene transfection. Morphological changes and the induction of various anti-apoptotic proteins were examined at the same time. Levels of HO-1 expression were variable in different clones of HO-1-transfected ECV304 cells. Among these, the clones with moderate levels of HO-1 expression were significantly more resistant to oxidative stress. In contrast, those with the highest levels of HO-1 exhibited paradoxically enhanced susceptibility to oxidative injury. Interestingly, the cell survival after oxidative stress was in parallel with the levels of Bcl-2 expression and of fibronectin receptor, alpha5 integrin. It is suggested from these results, that excessive HO-1 not only leads to enhanced cell injury, but also prolongs the repair process of the injured endothelial tissue. However, HO-1 reduces the oxidative cell injury and protects the endothelial cells, if its expression is appropriately controlled.
authors.affiliation: Department of Pediatrics, Angiogenesis and Vascular Development, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Maruhashi
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Kasahara
authors.forename: Kunio
authors.initials: K
authors.lastname: Ohta
authors.forename: Taizo
authors.initials: T
authors.lastname: Wada
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Ohta
authors.forename: Nami
authors.initials: N
authors.lastname: Nakamura
authors.forename: Tomoko
authors.initials: T
authors.lastname: Toma
authors.forename: Shoichi
authors.initials: S
authors.lastname: Koizumi
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yachie
mesh_terms: D000199:Actins / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D042783:Endothelial Cells; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D019254:Genes, bcl-2 / Q000502:physiology; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006427:Hemin / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D007150:Immunohistochemistry; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D008565:Membrane Proteins; D018384:Oxidative Stress / Q000502:physiology*
chemical_list: D000199:Actins; D039081:Integrin alpha5beta1; D008565:Membrane Proteins; D006427:Hemin; D006861:Hydrogen Peroxide; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1