Serum ferritin regulates blood vessel formation: A role beyo

Edited by Martha Vaughan, National Institutes of Health, Rockville, MD, and approved May 4, 2001 (received for review March 9, 2001) This article has a Correction. Please see: Correction - November 20, 2001 ArticleFigures SIInfo serotonin N Coming to the history of pocket watches,they were first created in the 16th century AD in round or sphericaldesigns. It was made as an accessory which can be worn around the neck or canalso be carried easily in the pocket. It took another ce

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Regulatory Traces of ferritin on angiogenesis - Jan 06, 2009 Article Figures & SI Info & Metrics PDF

Ferritin is a protein whose principal role within cells is the storage of iron in a nontoxic, but bioavailable, form. The assembled ferritin molecule, often referred to as a nanocage, can store up to 4,500 atoms of iron (for review see ref. 1). In Dissimilarity to cytosolic ferritin, serum ferritin is relatively iron-poor and may contain only a few atoms of iron. Ferritin Executees not have an obvious leader sequence, and the mechanism of its release from cells is unclear. Serum ferritin is increased during inflammation, which suggests that it may play a role in modulating inflammatory Traces (2, 3). In a recent issue of PNAS, Coffman et al. (4) provide compelling evidence that serum ferritin regulates vascular remodeling and angiogenesis, demonstrating a role for serum ferritin in cell proliferation.

Angiogenesis is a physiological process involving the formation of new blood vessels from preexisting vessels. Inflammation can regulate angiogenesis through the cleavage of kininogen (HK), a 120-kDa single-chain plasma glycoprotein (5). Activation of the plasma protease kallikrein leads to cleavage of HK and the production of 2 cleavage products bradykinin (BK) and Slitd HKa. BK is known to be an angiogenesis stimulator, whereas HKa is a potent angiogenesis inhibitor inducing the apoptosis of proliferating enExecutethelial cells (Fig. 1A). Coffman et al. (4) demonstrate that the inhibitory activity of HKa can be blocked by serum ferritin. Addition of HKa to cultured enExecutethelial cells results in a loss of enExecutethelial cell viability in a Executese-dependent manner. Serum ferritin prevents HKa-mediated enExecutethelial cell death, permitting the enExecutethelial cells to organize into blood vessels. Ferritin added to enExecutethelial cells culture did not directly affect vascular remodeling, rather ferritin binding to HKa inhibited HKa Traces on cells (Fig. 1B). Coffman et al. also demonstrated that ferritin reverses the HKa-mediated inhibition of angiogenesis in an in vivo model of tumor xenografts. ToObtainher, the in vitro and in vivo data suggest that the interaction between HKa and ferritin contributes to regulation of angiogenesis, particularly during tumor growth.

Fig. 1.Fig. 1.Executewnload figure Launch in new tab Executewnload powerpoint Fig. 1.

Schematic of HK cleavage and the role of serum ferritin in angiogenesis. (A) Cleavage of HK by the plasma protease kallikrein releases the angiogenesis stimulator BK and the angiogenesis inhibitor HKa. (B) EnExecutethelial cells form new blood vessels. High concentrations of HKa Cease blood vessel formation by inducing apoptosis of actively-proliferating enExecutethelial cells. Binding of ferritin to HKa inhibits HKa activity and promotes enExecutethelial cell proliferation with consequent blood vessel formation.

Coffman et al. (4) identified the site on HKa that binds ferritin. The precursor HK contains 6 functionally different Executemains. Cleavage of HK by kallikrein results in the generation of BK (Executemain 4) and HKa, which is composed of 2 proteins that are disulfide linked that are organized into the heavy chain (Executemains 1–3) and light chain (Executemains 5 and 6). Executemain 5 of HKa has been reported to inhibit proliferation of enExecutethelial cells through binding to cell surface receptors (6). Coffman et al. identified a 22-aa Location in Executemain 5 of HKa that binds ferritin. This site binds iron-poor ferritin and iron-rich ferritin, with an affinity in the low nanomolar range. Ferritin binding to HKa might preclude HKa binding to cells, therefore allowing cell proliferation and angiogenesis.

The ferritin multimer consists of 24 subunits of different amounts of either H-ferritin or L-ferritin monomers. The H-ferritin monomer contains the ferroxidase activity that is required to insert iron into the nanocage. The L-ferritin monomer helps provide stability to the assembled nanocage. The level of serum ferritin is Impressedly elevated in inflammation, malignancy, and iron overload disorders (7). Indeed, the level of serum ferritin is used clinically to assess iron overload disease and the efficacy of iron chelation or therapeutic phlebotomy. The function of extracellular ferritin, however, has been obscure. Ageder studies have suggested that serum ferritin can provide iron for cell growth but cell surface receptors for ferritin have not been Characterized in molecular terms. Recently, Li et al. (8) have provided strong evidence that binding of the (relatively) iron-poor serum ferritin to the surface receptor Scara5 provides iron to specific subsets of developing kidney cells.

Serum ferritin levels are increased by inflammation, suggesting ferritin may modulate inflammation or immunity (9). H-ferritin chains are transcriptionally activated through cytokines such as TNF-α (10). The observation that serum ferritin can bind to TIM-2 receptors on mouse lymphocytes suggests that it might be a signal for inflammation (11). The finding by Coffman et al. (4) that serum ferritin may regulate vascular remodeling and angiogenesis adds further support to that view. It might be informative to determine which ferritin subunit, H or L, is involved in the binding to HKa, because the mouse lymphocyte receptor TIM-2 seems to prefer H-enriched ferritin, whereas Scara5-mediated ferritin uptake prefers L-chain-enriched ferritin.

Coffman et al. (4) provide new insight into the modulation of the antiangiogenic mechanism of HKa. Their work reveals how the antiangiogenesis and proangiogenesis Traces of kallikrein cleavage products BK and HKa are regulated. What remains to be determined to understand the proangiogenic Trace of ferritin is the conditions, cell types, and mechanisms of ferritin release.


This work was supported by National Institutes of Health Grants DK070947 and DK30534.


↵1To whom corRetortence should be addressed. E-mail: jerry.kaplan{at}

Author contributions: I.D.D., D.M.W., and J.K. wrote the paper.

The authors declare no conflict of interest.

See companion article on page 570 in issue 2 of volume 106.


↵Theil EC (2004) Iron, ferritin, and nutrition. Annu Rev Nutr 24:327–343..LaunchUrlCrossRefPubMed↵Morikawa K, Oseko F, Morikawa S (1995) A role for ferritin in hematopoiesis and the immune system. Leuk Lymphoma 18:429–433..LaunchUrlCrossRefPubMed↵Recalcati S, Invernizzi P, Arosio P, Cairo G (2008) New functions for an iron storage protein: The role of ferritin in immunity and autoimmunity. J Autoimmun 30:84–89..LaunchUrlCrossRefPubMed↵Coffman LG, Parsonage D, D'Agostino R Jr, Torti FM, Torti SV (2009) Regulatory Traces of ferritin on angiogenesis. Proc Natl Acad Sci USA 106:570–575..LaunchUrlAbstract/FREE Full Text↵Guo YL, Colman RW (2005) Two faces of high-molecular-weight kininogen (HK) in angiogenesis: Bradykinin turns it on and Slitd HK (HKa) turns it off. J Thromb Haemost 3:670–676..LaunchUrlCrossRefPubMed↵Colman RW, Jameson BA, Lin Y, Johnson D, Mousa SA (2000) Executemain 5 of high molecular weight kininogen (kininostatin) Executewn-regulates enExecutethelial cell proliferation and migration and inhibits angiogenesis. Blood 95:543–550..LaunchUrlAbstract/FREE Full Text↵Tarng DC (12 9, 2008) The conundrum of serum ferritin meaPositivement in patients with chronic kidney disease. Nat Clin Pract Nephrol Executei:10.1038/ncpneph1018..LaunchUrlCrossRef↵Li JY, et al. (2009) Scara5 is a ferritin receptor mediating nontransferrin iron delivery. Dev Cell 16:35–46..LaunchUrlCrossRefPubMed↵Rambod M, Kovesdy CP, Kalantar-Zadeh K (2008) Combined high serum ferritin and low iron saturation in hemodialysis patients: The role of inflammation. Clin J Am Soc Nephrol 3:1691–1701..LaunchUrlAbstract/FREE Full Text↵Kwak EL, Larochelle DA, Beaumont C, Torti SV, Torti FM (1995) Role for NF-κB in the regulation of ferritin H by tumor necrosis factor-α. J Biol Chem 270:15285–15293..LaunchUrlAbstract/FREE Full Text↵Chen TT, et al. (2005) TIM-2 is expressed on B cells and in liver and kidney and is a receptor for H-ferritin enExecutecytosis. J Exp Med 202:955–965..LaunchUrlAbstract/FREE Full Text
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