Abstract
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 microm (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 microm iron led to an increase of approximately 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 microm) 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 microm) 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.
Highlights
Mature elastic fibers and laminae provide extensibility and elastic recoil to vascular walls and ligaments and form a connective tissue framework of lungs, elastic cartilage, and skin [1, 2]
The Influence of Iron on Elastin mRNA Levels and Message Stability—Because we have shown that incubation of fibroblasts with low (2–20 M) and high (200 M) iron concentrations induced opposite effects on the net deposition of insoluble elastin and that 2–200 M iron concentrations did not stimulate elastolytic activity of serine proteinases, we attempted to identify the level on which fluctuations in iron level would affect elastogenesis
Impaired elastic fibers have been detected in patients with -thalassaemia and in other inherited hemolytic disorders characterized with fluctuating iron levels [30, 32, 34, 58], no pathophysiological link between these two clinical features have ever been disclosed
Summary
Our experimental evidence demonstrates the existence of an opposite effect, in which higher, but not cytotoxic concentrations of iron (100 – 400 M) 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. Iron and Elastogenesis increase in the steady-state level of pro-␣2(I)-collagen in hepatocytes [39] and that 50 M iron treatment stimulated collagen gene expression in cultured stromal hepatic cells by inducing the synthesis and binding of Sp1 and Sp3 transcription factors to two regulatory elements located in the collagen ␣1 (I) promoter region [40]. We tested the influence of different iron concentrations on generation of intracellular ROS, and attempted to identify on which level these ironinduced ROS affect elastogenesis
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