Heme oxygenase-1 expression enhances vascular endothelial resistance to complement-mediated injury through induction of decay-accelerating factor: a role for increased bilirubin and ferritin

Abstract

Catabolism of free heme by heme oxygenase-1 (HO-1) generates carbon monoxide, biliverdin, and free iron (Fe). These end-products are responsible for much of the biologic activity of HO-1, including anti-inflammatory, antiapoptotic, antiproliferative, and antioxidant effects. We have identified an additional cytoprotective action, the regulation of complement activation, mediated via induction of decay-accelerating factor (DAF) . IntroductionVascular endothelial cells (ECs) express constitutive and inducible cytoprotective genes, which exert cytoprotective and antiinflammatory effects, maintain vascular integrity, and assist in endothelial repair. 1 Vascular endothelial growth factor (VEGF) plays an important role in the maintenance of these pathways in the normal adult vasculature. This notion is supported by the observation that VEGF up-regulates expression of several protective genes in EC, including endothelial nitric oxide synthase (eNOS), prostacyclin, and Bcl-2, and protects EC against oxidative stress. 2 Furthermore, we have reported that VEGF induces the expression of the cytoprotective, anti-inflammatory enzyme heme oxygenase-1 (HO-1) 3 and the complement inhibitory protein decay-accelerating factor (DAF). 4 HO-1 is the inducible form of the heme oxygenase system, acting as the rate-limiting factor in the catabolism of heme into biliverdin, releasing free iron (Fe) and carbon monoxide (CO). 5 Biliverdin is subsequently converted to bilirubin by biliverdin reductase, whereas intracellular Fe induces expression of the iron-binding protein heavy-chain ferritin 6 and the opening of Fe 2ϩ -export channels. 7 The importance of HO-1 in vasculoprotection is demonstrated by the severe and persistent endothelial damage observed in human HO-1 deficiency 8 and Hmox1 Ϫ/Ϫ mice. 9 HO-1 exerts a potent protective effect against atherogenesis, 10 cardiac ischemia/reperfusion injury, 11 and both graft rejection and accelerated arteriosclerosis after transplantation. [12][13][14] The complement cascade provides an innate defense mechanism against bacterial infection, bridging innate and adaptive immunity while affording clearance of antibody immune complexes. However, by the nature of its cytolytic effects, complement has the potential to inflict injury on bystander host tissues, including vascular endothelium. C3a, C5a, and the C5b-9 membrane attack complex (MAC) exert a variety of effects, including cytokine release, induction of cellular adhesion molecules, leukocyte adhesion, and generation of a prothrombotic endothelial surface. 15,16 Hence, complement activation has been implicated in the pathogenesis of atherosclerosis and the rejection of transplanted organs.Mechanisms for the control of complement activation on the surface of human cells include membrane-bound regulatory proteins: DAF (CD55), membrane cofactor protein (MCP; CD46), and CD59. In addition, murine cells express complement receptorrelated protein-Y (Crry/p65), which combines the functions of DAF and MCP. Membrane-bound human DAF prevents the formation...

Decreased Serum Bilirubin Is Associated With Silent Cerebral Infarction

“…20 In addition, our previous studies have observed that serum bilirubin has a tight correlation with baPWV. Furthermore, baPWV has been used as an index of subclinical atherosclerosis.…”

“…19 Moreover, heme oxygenase 1 and heme degradation products could attenuate complement-mediated acute inflammation and protect human vascular endothelial cells against complement-mediated injury. 20 In addition, our previous studies have observed that serum bilirubin has a tight correlation with baPWV. Furthermore, baPWV has been used as an index of subclinical atherosclerosis.…”

Heme Induces Heme Oxygenase 1 via Nrf2

“…Heme suppressed macrophage hROS ( Figure 4A), and this protection was strongly reversed in the presence of the specific HO-1 inhibitor 10 mol/L zinc protoporphyrin 19,20 ( Figure 4B). Zinc protoporphyrin also reduced macrophage survival in culture over 6 days, whereas both heme and the specific HO-1 activator cobalt protoporphyrin 19,20 had the opposite effect, each in a concentration-dependent manner over 100 nmol/L to 10 mol/L ( Figure 4C). Furthermore, both the increase in CD163 and suppression of HLA-DR induced by heme were antagonized by zinc protoporphyrin (300 nmol/L-3 mol/L) ( Figure 4D).…”

Complement—here, there and everywhere, but what about the transplanted organ?

“…Cultured human ECs upregulate CD55 and CD59 when stimulated with pathogenic antibodies, C5b-C9, thrombin and other pro-inflammatory molecules such as TNF [109,110]. Other studies suggest antiapoptotic proteins such as BCL-2 and haem oxygenase 1 (HO1) upregulate CD55 thereby enhancing endothelial resistance and promoting accommodation of the graft [111]. ECs also modulate T cell function and expansion through local production of complement and CD88 signalling on T cells seen in heart and kidney transplantation models [112,113].…”