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Ferritin Prevents Calcification and Osteoblastic Differentiation of Vascular Smooth Muscle Cells

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Ferritin Prevents Calcification and Osteoblastic Differentiation of Vascular Smooth Muscle Cells BASIC RESEARCH www.jasn.org Ferritin Prevents Calcification and Osteoblastic Differentiation of Vascular Smooth Muscle Cells Abolfazl Zarjou,* Vikto´ria Jeney,* Paolo Arosio,† Maura Poli,† Pe´ter Antal-Szalma´s,‡ ʈ Anupam Agarwal,§ Gyo¨rgy Balla, and Jo´zsef Balla* ʈ Departments of *Medicine, ‡Clinical Biochemistry and Molecular Pathology, and Pediatrics, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary; †Dipartimento Materno Infantile e Tecnologie Biomediche, University of Brescia, Brescia, Italy; and §Department of Medicine, Nephrology Research and Training Center and Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama ABSTRACT Vascular calcification plays a role in the pathogenesis of atherosclerosis, diabetes, and chronic kidney disease. Human aortic smooth muscle cells (HSMCs) undergo mineralization in response to elevated levels of inorganic phosphate (Pi) in an active and well-regulated process. This process involves increased activity of alkaline phosphatase and increased expression of core binding factor ␣-1, a bone-specific transcription factor, with the subsequent induction of osteocalcin. Mounting evidence suggests an essential role for the heme oxygenase 1 (HO-1)/ferritin system to maintain homeostasis of vascular function. We examined whether induction of HO-1 and ferritin alters mineralization of HSMCs provoked by high Pi. Upregulation of the HO-1/ferritin system inhibited HSMC calcification and osteoblastic differentiation. Of the products of the system, only ferritin and, to a lesser extent, biliverdin were responsible for the inhibition. Ferritin heavy chain and ceruloplasmin, which both possess ferroxidase activity, inhibited calcification; a site-directed mutant of ferritin heavy chain, which lacked ferroxidase activity, failed to inhibit calcification. In addition, osteoblastic transformation of HSMCs provoked by elevated Pi (assessed by upregulation of core binding factor ␣-1, osteocalcin, and alkaline phosphatase activity) was diminished by ferritin/ferroxidase activity. We conclude that induction of the HO-1/ferritin system prevents Pi-mediated calcification and osteoblastic differentiation of human smooth muscle cells mainly via the ferroxidase activity of ferritin. J Am Soc Nephrol 20: 1254–1263, 2009. doi: 10.1681/ASN.2008070788 Vascular calcification occurs in many pathologic tion follows two distinct patterns: (1) Intimal calci- conditions and can lead to devastating clinical con- fication that occurs with atherosclerotic plaques sequences. For example, it has been related to in- and (2) medial calcification, which is characterized creased risk for cardiovascular morbidities and by diffuse calcification of the media, particularly at complications such as atherosclerotic plaque bur- den,1–3 myocardial infarction,4,5 coronary artery Received July 26, 2008. Accepted January 22, 2009. disease,6,7 postangioplasty dissection,8 and in- creased ischemic episodes in peripheral vascular Published online ahead of print. Publication date available at www.jasn.org. disease.9 Studies also have indicated that coronary calcification may be predictive of or associated with A.Z. and V.J. contributed equally to this work. sudden cardiac death.10,11 Indeed, coronary calcifi- G.B. and J.B. contributed equally to this work. cation score measured by electron beam computed Correspondence: Dr. Jo´zsef Balla, Pf. 19, Nagyerdei krt. 98, tomography has been shown to have a prognostic 4012 Debrecen, Hungary. Phone/Fax: 36-52-413-653; E-mail: value for cardiovascular events comparable to that [email protected] of the Framingham risk index.11 Vascular calcifica- Copyright ᮊ 2009 by the American Society of Nephrology 1254 ISSN : 1046-6673/2006-1254 J Am Soc Nephrol 20: 1254–1263, 2009 www.jasn.org BASIC RESEARCH the level of the internal elastic lamina, that does not necessarily accompany atherosclerosis. This pattern is commonly seen in patients with chronic kidney disease (CKD), who commonly exhibit hyperphosphatemia. The mechanism of vascular calci- fication is not completely understood, although abnormalities in mineral metabolism are considered important risk factors. Many studies have demonstrated the role of high extracel- lular inorganic phosphate (Pi) to induce calcification of vascu- lar cells in vitro12–16 in a process mediated by a sodium-depen- dent phosphate co-transporter that facilitates entry of Pi into vascular cells.17 This induces transition of human aortic smooth muscle cells (HSMCs) into osteoblast-like cells through a process that is accompanied by increased expression of core binding factor ␣-1 (Cbfa-1), which is an osteoblast- specific transcription factor required for osteoblast differenti- ation, bone matrix gene expression, and, consequently, bone mineralization.18 There is also an upregulation of alkaline phosphatase (ALP), an important enzyme in early osteogenesis and osteocalcin, a major noncollagenous protein found in bone matrix that is believed to regulate mineralization.19 Heme is a ubiquitous iron-containing molecule that is an absolute necessity for aerobic life. Current evidence suggests that heme can be pro-oxidant and potentially toxic.20–22 Heme induces the synthesis of heme oxygenase 1 (HO-1), the rate- limiting enzyme in the catabolism of heme.23 HO cleaves the porphyrin ring at the ␣-methene bridge to form biliverdin and carbon monoxide and releases free redox active iron. Biliver- Figure 1. Heme inhibits HSMC calcification induced by elevated din is then converted to bilirubin by biliverdin reductase. Pi in a dosage-dependent manner. (A) HSMCs were cultured in Ferritin is another molecule strongly inducible by heme and GM (I) or in calcification medium in the absence (II) or presence of iron. This is an iron storage protein that exhibits antioxidant heme (50 ␮mol/L; III) for 9 d. Von Kossa staining of cells was properties, and it was shown to protect the endothelium performed as described in the Concise Methods section. Repre- against the damaging effects of heme and oxidants.24 Ferritin is sentative picture of three separate experiments. (B) HSMCs were a large (450 kD), spherical shell that can store up to 4500 Fe cultured in GM or in calcification medium alone or supplemented ␮ atoms in a safe, nontoxic form. It is made of 24 subunits of two with NaOH (Vehicle, 1 mmol/L) or 5, 25, and 50 mol/L heme types (heavy [H] and light [L] chain) whose proportion de- (dissolved in NaOH at a final concentration of 1 mmol/L in each group). Calcium contents of cells were measured after 3 (Ⅺ),6(u), pends on the iron status of the cell, the tissue, and the organ.25 and9d(f) of culture as described in the Concise Methods The H-chain has ferroxidase activity that is important not only section and were normalized by protein content. Data are for iron incorporation but also in controlling the potentially means Ϯ SD of three independent experiments performed in toxic Fe (II) ions, thereby reducing oxidative damage.26 duplicate. (C) HSMCs were cultured in GM alone or supple- In our investigations, we tested the role that heme may play mented with 2, 3, or 4 mmol/L Pi (F). The media containing in the process of extracellular calcification, and we observed different amounts of Pi was supplemented with heme (50 ␮mol/L; that heme decreases extracellular matrix calcification in a dos- Œ) or with NaOH (vehicle, 1 mmol/L; ‚). Calcium deposition was age-responsive manner. These observations prompted us to measured at day 9, and results were normalized by protein con- hypothesize that one or more products of heme catabolism tent of the cells. Data show the average of three separate exper- Ͻ Ͻ may inhibit HSMC mineralization. iments performed in duplicate. *P 0.05; **P 0.01. Magnifi- cation, ϫ100. RESULTS 1AI). Intriguing, we found that addition of heme (50 ␮mol/L, 9 d) to the calcification medium inhibited calcium deposition Heme Decreases HSMC Calcification in a Dosage- as shown by von Kossa staining (Figure 1AIII). Extracellular Responsive Manner calcium measurements showed that the inhibitory effect of To develop an in vitro model, we cultured HSMCs in calcifica- heme on extracellular calcification is dosage dependent, with a tion medium. Granular deposits developed in HSMCs grown highly significant (P Ͻ 0.01) suppression at a dosage of 25 in calcification medium for 9 d (Figure 1AII) but not in the ␮mol/L (Figure 1B). control culture grown in normal growth medium (GM; Figure Heme is a strong inducer of HO-1, and, as expected, we J Am Soc Nephrol 20: 1254–1263, 2009 Ferritin Prevents Calcification 1255 BASIC RESEARCH www.jasn.org found that HO-1 mRNA, protein, and HO activity were ele- vated in the cells cultured in heme-containing medium. Pi level of the medium did not affect this heme-mediated induction of HO-1 (Figure 2, A, C, and D). In addition, we found that heme did not significantly alter HO-2 expression (Figure 2B), and it induced expression of ferritin regardless of Pi level of the me- dium (Figure 2E). Ferritin and Ferroxidase Activity Attenuate HSMC Calcification Heme induces HO-1 and ferritin; therefore, it was of interest to analyze which of the two had a major effect on calcification. We also analyzed the role of the end products of HO catalyzed heme degradation by adding them exogenously to the calcifi- cation medium. We found that iron, regardless of its ferric or ferrous state (50 ␮mol/L), completely inhibits calcification (the ferrous state, data not shown). Biliverdin at the concen- tration of 50 ␮mol/L provided a little but significant (P Ͻ 0.05) decrease in calcification (Figure 3A). Addition of CO (1%) or bilirubin (50 ␮mol/L) did not influence calcification (Figure 3A). Conversely, addition of apoferritin (2 mg/ml) or recom- binant H-chain ferritin to the calcification medium abolished calcification (Figure 3B). These two ferritin types have ferroxi- dase activity; therefore, we tested another protein with ferroxi- dase activity, ceruloplasmin. Ceruloplasmin was found to mimic the effect of ferritins at a concentration of 4 mg/ml. The protective effect of L-ferritin was minor compared with that of H-ferritin and ceruplasmin.
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