Heme Induces the Expression of Adhesion Molecules ICAM-1, VCAM-1, and E Selectin in Vascular Endothelial Cells

Wagener, Frank A. D. T. G.; Feldman, Esther; Witte, T.J.M. de; Abraham, Nader G.

doi:10.3181/00379727-216-44197

Cited by 217 publications

(173 citation statements)

References 30 publications

Supporting

Mentioning

166

Contrasting

Unclassified

Order By: Relevance

“…Free heme is lipophilic and intercalates into the membrane of endothelial cells increasing vascular permeability and ICAM-1, VCAM-1, and E-selectin expression (19). As a consequence, infused heme (hemin) has been demonstrated to enhance leukocyte adhesion to the vessel wall (17,18), a finding confirmed in the current study.…”

Section: Discussionsupporting

confidence: 78%

Erythrocyte Hemolysis and Hemoglobin Oxidation Promote Ferric Chloride-induced Vascular Injury

Woollard

Sturgeon

Chin-Dusting

et al. 2009

Journal of Biological Chemistry

106

View full text Add to dashboard Cite

The release of redox-active iron and heme into the bloodstream is toxic to the vasculature, contributing to the development of vascular diseases. How iron induces endothelial injury remains ill defined. To investigate this, we developed a novel ex vivo perfusion chamber that enables direct analysis of the effects of FeCl 3 on the vasculature. We demonstrate that FeCl 3 treatment of isolated mouse aorta, perfused with whole blood, was associated with endothelial denudation, collagen exposure, and occlusive thrombus formation. Strikingly exposing vessels to FeCl 3 alone, in the absence of perfused blood, was associated with only minor vascular injury. Whole blood fractionation studies revealed that FeCl 3 -induced vascular injury was red blood cell (erythrocyte)-dependent, requiring erythrocyte hemolysis and hemoglobin oxidation for endothelial denudation. Overall these studies define a unique mechanism of Fe 3؉ -induced vascular injury that has implications for the understanding of FeCl 3 -dependent models of thrombosis and vascular dysfunction associated with severe intravascular hemolysis.Iron and heme-containing moieties are indispensable for the normal transport of oxygen in the blood; however, once released into the bloodstream these molecules are highly toxic to the vasculature because of their pro-oxidative effects on the endothelium (1-3). Humans have therefore evolved sophisticated iron transport and sequestration systems as well as hememetabolizing enzymes to rapidly clear iron and heme from the circulation (4, 5). There is growing evidence that defects in these natural protective mechanisms lead to endothelial dysfunction and vascular disease, and as a consequence, methods that reduce the pro-oxidative effects of iron and heme may have therapeutic benefit (2).Clinical syndromes associated with marked intravascular hemolysis and circulating free hemoglobin, such as sickle cell disease, paroxysmal nocturnal hemoglobinuria, thalassemias, and hereditary spherocytosis, lead to endothelial dysfunction, thrombosis, and vascular disease (5-10). Similarly administration of purified recombinant hemoglobin to humans promotes vascular injury and arterial thrombosis, precipitating acute myocardial infarction (11-13). Some of these vascular effects are related to nitric oxide scavenging by excess plasma hemoglobin, whereas others are linked to cytotoxic, proinflammatory, and pro-oxidant effects of iron-containing hemoglobin and heme (14 -19). Interestingly elevated levels of body iron stores are associated with an increased risk of myocardial infarction, and carriers of the hemochromatosis gene have an increased risk of myocardial infarction and cardiovascular death (20,21). Whether the pro-oxidative effects of iron per se are proatherogenic remains controversial; however, in the context of erythrocyte-dependent release of hemoglobin and heme, redox-active iron is likely to play an important role in promoting vascular dysfunction.The well defined pro-oxidative properties of redox-active iron have been exploited expe...

show abstract

Section: Discussionsupporting

confidence: 78%

Erythrocyte Hemolysis and Hemoglobin Oxidation Promote Ferric Chloride-induced Vascular Injury

Woollard

Sturgeon

Chin-Dusting

et al. 2009

Journal of Biological Chemistry

106

View full text Add to dashboard Cite

show abstract

“…When HO-1 activity is suppressed, proinflammatory heme would accumulate and trigger endothelial cell activation and the expression of proinflammatory genes presumably involved in the pathogenesis of graft rejection (33). An alternative but not mutually exclusive explanation would be that HO enzymatic activity is needed to generate one or more of the end-products of heme catabolism, e.g.…”

Section: Discussionmentioning

confidence: 99%

Carbon Monoxide Generated by Heme Oxygenase-1 Suppresses the Rejection of Mouse-to-Rat Cardiac Transplants

Sato

Balla

Otterbein

et al. 2001

The Journal of Immunology

440

338

View full text Add to dashboard Cite

Mouse-to-rat cardiac transplants survive long term after transient complement depletion by cobra venom factor and T cell immunosuppression by cyclosporin A. Expression of heme oxygenase-1 (HO-1) by the graft vasculature is critical to achieve graft survival. In the present study, we asked whether this protective effect was attributable to the generation of one of the catabolic products of HO-1, carbon monoxide (CO). Our present data suggests that this is the case. Under the same immunosuppressive regimen that allows mouse-to-rat cardiac transplants to survive long term (i.e., cobra venom factor plus cyclosporin A), inhibition of HO-1 activity by tin protoporphyrin, caused graft rejection in 3–7 days. Rejection was associated with widespread platelet sequestration, thrombosis of coronary arterioles, myocardial infarction, and apoptosis of endothelial cells as well as cardiac myocytes. Under inhibition of HO-1 activity by tin protoporphyrin, exogenous CO suppressed graft rejection and restored long-term graft survival. This effect of CO was associated with inhibition of platelet aggregation, thrombosis, myocardial infarction, and apoptosis. We also found that expression of HO-1 by endothelial cells in vitro inhibits platelet aggregation and protects endothelial cells from apoptosis. Both these actions of HO-1 are mediated through the generation of CO. These data suggests that HO-1 suppresses the rejection of mouse-to-rat cardiac transplants through a mechanism that involves the generation of CO. Presumably CO suppresses graft rejection by inhibiting platelet aggregation that facilitates vascular thrombosis and myocardial infarction. Additional mechanisms by which CO overcomes graft rejection may involve its ability to suppress endothelial cell apoptosis.

show abstract

“…Heme catalyzes the formation of reactive oxygen species (ROS), and heme released from intracellular hemoproteins is an important source of redox active iron [15]. ROS created in the presence of heme are capable of damaging proteins, lipids and DNA [119,[124][125][126][127]. Heme is a lipophilic molecule that can easily cross cell membranes and gain entry to cells [15].…”

Section: Dysregulation Of Heme Levels Can Cause Serious Diseasesmentioning

confidence: 99%

Heme: a versatile signaling molecule controlling the activities of diverse regulators ranging from transcription factors to MAP kinases

2006

View full text Add to dashboard Cite

Heme Induces the Expression of Adhesion Molecules ICAM-1, VCAM-1, and E Selectin in Vascular Endothelial Cells

Abstract: Heme is an important immunostimulating agent and oxidative factor con tributing to endothelial cell activation. To investigate the mechanism of heme-induced endothelial cel! activation, we analyzed the effect of heme and the inflammatory cy tokine, tumor necrosis facto r-a (TNF- Show more

Cited by 217 publications

References 30 publications

Erythrocyte Hemolysis and Hemoglobin Oxidation Promote Ferric Chloride-induced Vascular Injury

Erythrocyte Hemolysis and Hemoglobin Oxidation Promote Ferric Chloride-induced Vascular Injury

Carbon Monoxide Generated by Heme Oxygenase-1 Suppresses the Rejection of Mouse-to-Rat Cardiac Transplants

Heme: a versatile signaling molecule controlling the activities of diverse regulators ranging from transcription factors to MAP kinases

Contact Info

Product

Resources

About