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(Ϫ/Ϫ)] 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(Ϫ/Ϫ) 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(Ϫ/Ϫ) mAEC showed a 2-fold reduction in HO activity and marked increases in levels of gp91 phox /NADPH oxidase isoform, superoxide, nuclear factor B activation, and expression of inflammatory cytokines, including interleukin (IL)-1␣ 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(Ϫ/Ϫ) cells attenuated angiogenesis and reduced superoxide production. This transformation underscores the importance of HO-2 in the regulation of endothelial cell homeostasis.The integrity of the vascular endothelium is critical for the maintenance of vascular homeostasis. This layer of cells actively participates in the regulation of vascular tone, blood fluidity, growth of vascular smooth muscle cells, and local inflammation by synthesizing and releasing paracrine factors in response to humoral, mechanical, and neural stimuli. Under normal conditions, the endothelium maintains a vasodilatory, antithrombotic, and anti-inflammatory state. One of the systems that contribute to the maintenance of this state is the heme-heme oxygenase (HO) system. HO is the rate-limiting enzyme in heme catabolism. It cleaves heme into iron, sequestered by ferritin, carbon monoxide (CO), and biliverdin, which is reduced to bilirubin by biliverdin reductase (Abraham and Kappas, 2008). Two isoforms, HO-1 and HO-2, are the major source of HO activity in most tissues. Both are alike in terms of mechanisms of heme oxidation, cofactor and substrate specificity, and susceptibility to inhibition by porphyrins (Maines, 1988;Abraham and Kappas, 2008). They differ in their postulated function; HO-2 functions as the constitutive HO activity contributing to cell homeostasis, whereas HO-1 expression is relatively low in most normal tissues. After injury, however, HO-1 expression is greatly enhanced to play a significant role in cytoprotection (Abraham and Kappas, 2008). The catalytic activity of HO is considered the underlying principle of HO cytoprotective actions. Heme functions as a double-edged sword in that in moderate quantities and when bound to protein, heme forms an essential element for ...

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Therapeutic Potential of Pegylated Hemin for Reactive Oxygen Species-Related Diseases via Induction of Heme Oxygenase-1: Results from a Rat Hepatic Ischemia/Reperfusion Injury Model

“…HO-2 is thus believed to contribute to normal housekeeping. And it has been reported that HO-2 behaves as a basal tone of anti-inflammatory signals, and deletion of HO-2 disables execution of the acute inflammatory and reparative response, leading to an exaggerated inflammatory response including increased oxidative stress and angiogenesis (Seta et al, 2006;Bellner et al, 2009). Moreover, it is known that HO-2 is induced by the treatment of corticosteroids (Maines et al, 1996), which is an important protective response during acute illness or stress, and is widely used as a treatment of inflammatory diseases.…”

Heme Oxygenase in the Regulation of Vascular Biology: From Molecular Mechanisms to Therapeutic Opportunities

“…In addition, mice deficient in HO-2 have revealed several important functions of this enzyme. For example, HO-2 deletion causes EC activation marked by oxidative stress, inflammation, and angiogenesis (23), which underscores the importance of HO-2 in the regulation of EC homeostasis. HO-2 deficiency disables execution of the acute inflammatory and reparative response after epithelial injury and leads to an exaggerated inflammatory response in antigen-induced peritonitis (231), implicating a role for HO-2 in the regulation of the inflammatory and reparative response to injury.…”