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J. Biol. Chem., Vol. 280, Issue 3, 2341-2351, January 21, 2005

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Fluctuations of Intracellular Iron Modulate Elastin Production^*

Severa Bunda, Nilo Kaviani, and Aleksander Hinek

From the Cardiovascular Research Program, The Hospital for Sick Children and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 1X8, Canada

Production of insoluble elastin, the major component of elastic fibers, can be modulated by numerous intrinsic and exogenous factors. Because patients with hemolytic disorders characterized with fluctuations in iron concentration demonstrate defective elastic fibers, we speculated that iron might also modulate elastogenesis. In the present report we demonstrate that treatment of cultured human skin fibroblasts with low concentration of iron 2–20 µM (ferric ammonium citrate) induced a significant increase in the synthesis of tropoelastin and deposition of insoluble elastin. Northern blot and real-time reverse transcription-PCR analysis revealed that treatment with 20 µM iron led to an increase of 3-fold in elastin mRNA levels. Because treatment with an intracellular iron chelator, desferrioxamine, caused a significant decrease in elastin mRNA level and consequent inhibition of elastin deposition, we conclude that iron facilitates elastin gene expression. Our experimental evidence also demonstrates the existence of an opposite effect, in which higher, but not cytotoxic concentrations of iron (100–400 µM) induced the production of intracellular reactive oxygen species that coincided with a significant decrease in elastin message stability and the disappearance of iron-dependent stimulatory effect on elastogenesis. This stimulatory elastogenic effect was reversed, however, in cultures simultaneously treated with high iron concentration (200 µM) and the intracellular hydroxyl radical scavenger, dimethylthiourea. Thus, presented data, for the first time, demonstrate the existence of two opposite iron-dependent mechanisms that may affect the steady state of elastin message. We speculate that extreme fluctuations in intracellular iron levels result in impaired elastic fiber production as observed in hemolytic diseases.

Received for publication, August 27, 2004 , and in revised form, November 8, 2004.

^* This work was supported by the Canadian Institute of Health Research (Grant PG 13920) and by the Stroke Foundation of Ontario (Grant NA 4381 and Career Investigator Award CI 4198 to A. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Cardiovascular Research Program, The Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. Tel.: 416-813-5918; Fax: 416-813-7480; E-mail: alek.hinek{at}sickkids.on.ca.

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