The source of heme for vascular heme oxygenase I: heme uptake in rat aorta

Abstract

During the last decade, heme oxygenase (HO) and carbon monoxide (CO) have garnered substantial research interest in terms of cell and organ regulation, especially as they bear on the central nervous system, organ transplantation, and the cardiovascular system. While the enzymatic mechanism, substrates, and products of HO are well known, it is not clear whether the cardiovascular system derives its supply of the heme substrate through de novo synthesis or uptake from the extracellular milieu. The objective of the present study was to test the latter possibility in rat aorta and to determine the influence of plasma proteins that bind heme in vivo, viz. hemopexin and albumin. Aortic tissue was exposed to [14C]heme in vitro, and the concentration and time dependence of heme uptake was assessed. The presence of hemopexin or albumin in the incubation medium dramatically decreased heme uptake by the aorta. Heme uptake by aortic tissue was not altered after induction of HO-1, which would be expected to increase tissue heme demand. In summary, the rat, isolated aorta was capable of obtaining heme from its external milieu, but this was obtunded in the presence of the plasma proteins hemopexin or albumin. For normal physiological situations, heme uptake may not be a usual source of substrate for vascular HO and hemoenzymes such as nitric oxide synthase, soluble guanylyl cyclase, and cyclooxygenase.

Hemopexin decreases hemin accumulation and catabolism by neural cells

“…This result is consistent with those of Balla et al in porcine aortic endothelial cells (Balla et al, 1991), Taketani et al in hepatocytes (Taketani et al, 1998), and Bui et al in aortic tissue in vitro (Bui et al, 2004), and likely explains the attenuation of hemin-mediated HO-1 induction by hemopexin. The best-characterized mechanism of cellular heme uptake is via receptor mediated endocytosis of the heme-hemopexin complex by the low density lipoprotein receptor - related protein 1 (LRP1), which is expressed by hepatocytes and to a lesser extent by a variety of cell types including neurons (Ishiguro et al, 1995).…”

The Interaction of Nitric Oxide with Distinct Hemoglobins Differentially Amplifies Endothelial Heme Uptake and Heme Oxygenase-1 Expression

“…It is known that albumin binds heme, and it was not surprising to observe that the presence of this protein decreased heme incorporation in a concentration-dependent manner (Fig. 6B), as already reported for rat aorta (Bui et al, 2004). The addition of AS enhanced heme uptake even in the presence of albumin.…”

Hemopexin and haptoglobin: allies against heme toxicity from hemoglobin not contenders

“…Only HPX, not Hp, inhibited hemin-stimulated lipid peroxidation providing direct evidence for HPX as the primary extracellular antioxidant protector against heme toxicity in biological fluids (Gutteridge and Smith, 1988 ). There are numerous examples of this: HPX prevents heme uptake into the aorta (Bui et al, 2004 ) and endothelial cells while targeting heme to the liver (Smith and Morgan, 1979 ).…”