Heme oxygenase-2 deletion causes endothelial cell activation marked by oxidative stress, inflammation, and angiogenesis.

Abstract

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.

• Authors: Lars Bellner, Lucia Martinelli, Adna Halilovic, Kiran Patil, Nitin Puri, Michael W Dunn, Raymond F Regan, Michal Laniado Schwartzman
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 331 Issue 3 Pg. 925-32 (Dec 2009) ISSN: 1521-0103 [Electronic] United States
• PMID: 19773531 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• NF-kappa B
• Vascular Endothelial Growth Factor A
• Superoxides
• Heme Oxygenase (Decyclizing)
• heme oxygenase-2
• Receptors, Vascular Endothelial Growth Factor

Topics

• Animals
• Blotting, Western
• Cells, Cultured
• Endothelial Cells (enzymology, metabolism)
• Endothelium, Vascular (enzymology, metabolism, pathology)
• Gene Deletion
• Heme Oxygenase (Decyclizing) (deficiency, genetics, metabolism)
• Inflammation (enzymology, genetics, immunology, metabolism)
• Mice
• Mice, Knockout
• Microscopy, Fluorescence
• NF-kappa B (immunology)
• Neovascularization, Pathologic (enzymology, genetics, metabolism)
• Oxidative Stress (genetics)
• Receptors, Vascular Endothelial Growth Factor (biosynthesis)
• Superoxides (metabolism)
• Vascular Endothelial Growth Factor A (biosynthesis)