Heme oxygenase-2 deletion causes endothelial cell activation marked by oxidative stress, inflammation, and angiogenesis.
In previous studies, we have shown that heme oxygenase (HO)-2 null [HO-2(-/-)] mice exhibit a faulty response to injury; chronic inflammation and massive neovascularization replaced resolution of inflammation and tissue repair. Endothelial cells play an active and essential role in the control of inflammation and the process of angiogenesis. We examined whether HO-2 deletion affects endothelial cell function. Under basal conditions, HO-2(-/-) aortic endothelial cells (mAEC) showed a 3-fold higher expression of vascular endothelial growth factor receptor 1 and a marked angiogenic response compared with wild-type (WT) cells. Compared with WT cells, HO-2(-/-) mAEC showed a 2-fold reduction in HO activity and marked increases in levels of gp91(phox)/NADPH oxidase isoform, superoxide, nuclear factor kappaB activation, and expression of inflammatory cytokines, including interleukin (IL)-1alpha and IL-6. HO-2 deletion transforms endothelial cells from a "normal" to an "activated" phenotype characterized by increases in inflammatory, oxidative, and angiogenic factors. This switch may be the result of reduced HO activity and the associated reduction in the cytoprotective HO products, carbon monoxide and biliverdin/bilirubin, because addition of biliverdin to HO-2(-/-) cells attenuated angiogenesis and reduced superoxide production. This transformation underscores the importance of HO-2 in the regulation of endothelial cell homeostasis.
Department of Pharmacology, New York Medical College, Valhalla, New York 10595, USA.
Lars
L
Bellner
Lucia
L
Martinelli
Adna
A
Halilovic
Kiran
K
Patil
Nitin
N
Puri
Michael W
MW
Dunn
Raymond F
RF
Regan
Michal Laniado
ML
Schwartzman
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000201:enzymology* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D006419:Heme Oxygenase (Decyclizing) / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D016328:NF-kappa B / Q000276:immunology; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor / Q000096:biosynthesis; D013481:Superoxides / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D016328:NF-kappa B; D042461:Vascular Endothelial Growth Factor A; D013481:Superoxides; D006419:Heme Oxygenase (Decyclizing); C105245:heme oxygenase-2; D040262:Receptors, Vascular Endothelial Growth Factor