Ferritin prevents calcification and osteoblastic differentiation of vascular smooth muscle cells.
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 alpha-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 alpha-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.
Department of Medicine, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.
Abolfazl
A
Zarjou
Viktória
V
Jeney
Paolo
P
Arosio
Maura
M
Poli
Péter
P
Antal-Szalmás
Anupam
A
Agarwal
György
G
Balla
József
J
Balla
D002113:Calcification, Physiologic; D002454:Cell Differentiation; D002478:Cells, Cultured; D002570:Ceruloplasmin / Q000378:metabolism; D005293:Ferritins / Q000502:physiology*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000502:physiology*; D010006:Osteoblasts / Q000166:cytology; D015675:Osteocalcin / Q000378:metabolism
D015675:Osteocalcin; D005293:Ferritins; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D002570:Ceruloplasmin