Ferritin Prevents Calcification and Osteoblastic Differentiation of Vascular Smooth Muscle Cells
Open Access
- 1 June 2009
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of the American Society of Nephrology
- Vol. 20 (6), 1254-1263
- https://doi.org/10.1681/asn.2008070788
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 α-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 α-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.Keywords
This publication has 43 references indexed in Scilit:
- Anemia of chronic disease: A harmful disorder or an adaptive, beneficial response?CMAJ : Canadian Medical Association Journal, 2008
- Phosphate Is a Uremic ToxinJournal of Renal Nutrition, 2008
- Heme Oxygenase-1Circulation, 2006
- Vascular CalcificationCirculation Research, 2006
- The Heme Oxygenase System: Update 2005Antioxidants and Redox Signaling, 2005
- Vascular CalcificationJournal of the American Society of Nephrology, 2003
- Intracellular targets in heme protein-induced renal injuryKidney International, 1998
- β-Glycerophosphate Accelerates Calcification in Cultured Bovine Vascular Smooth Muscle CellsArteriosclerosis, Thrombosis, and Vascular Biology, 1995
- Derepression of Ferritin Mmessenger RNA Translation by Hemin in VitroScience, 1990
- The Ferritin Family of Iron Storage ProteinsAdvances in enzymology and related subjects of biochemistry, 1990