Pharmacological induction of ferritin prevents osteoblastic transformation of smooth muscle cells.
Vascular calcification is a frequent complication of atherosclerosis, diabetes and chronic kidney disease. In the latter group of patients, calcification is commonly seen in tunica media where smooth muscle cells (SMC) undergo osteoblastic transformation. Risk factors such as elevated phosphorus levels and vitamin D3 analogues have been identified. In the light of earlier observations by our group and others, we sought to inhibit SMC calcification via induction of ferritin. Human aortic SMC were cultured using β-glycerophosphate with activated vitamin D3 , or inorganic phosphate with calcium, and induction of alkaline phosphatase (ALP) and osteocalcin as well as accumulation of calcium were used to monitor osteoblastic transformation. In addition, to examine the role of vitamin D3 analogues, plasma samples from patients on haemodialysis who had received calcitriol or paricalcitol were tested for their tendency to induce calcification of SMC. Addition of exogenous ferritin mitigates the transformation of SMC into osteoblast-like cells. Importantly, pharmacological induction of heavy chain ferritin by 3H-1,2-Dithiole-3-thione was able to inhibit the SMC transition into osteoblast-like cells and calcification of extracellular matrix. Plasma samples collected from patients after the administration of activated vitamin D3 caused significantly increased ALP activity in SMC compared to the samples drawn prior to activated vitamin D3 and here, again induction of ferritin diminished the osteoblastic transformation. Our data suggests that pharmacological induction of ferritin prevents osteoblastic transformation of SMC. Hence, utilization of such agents that will cause enhanced ferritin synthesis may have important clinical applications in prevention of vascular calcification.
Faculty of Medicine, Division of Nephrology, Department of Internal Medicine, University of Debrecen, Debrecen, Hungary.
Gergely
G
Becs
Division of Nephrology, Department of Medicine, Nephrology Research and Training Center and Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA.
Abolfazl
A
Zarjou
Division of Nephrology, Department of Medicine, Nephrology Research and Training Center and Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA.
Anupam
A
Agarwal
Faculty of Medicine, Division of Nephrology, Department of Internal Medicine, University of Debrecen, Debrecen, Hungary.
Katalin Éva
KÉ
Kovács
Faculty of Medicine, Division of Nephrology, Department of Internal Medicine, University of Debrecen, Debrecen, Hungary.
Ádám
Á
Becs
Faculty of Medicine, Division of Nephrology, Department of Internal Medicine, University of Debrecen, Debrecen, Hungary.
Mónika
M
Nyitrai
Faculty of Medicine, Division of Neonatology, Department of Pediatrics, University of Debrecen, Debrecen, Hungary.
Enikő
E
Balogh
Faculty of Medicine, Division of Neonatology, Department of Pediatrics, University of Debrecen, Debrecen, Hungary.
Emese
E
Bányai
Molecular Targets Program, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
John W
JW
Eaton
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Paolo
P
Arosio
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Maura
M
Poli
Faculty of Medicine, Division of Nephrology, Department of Internal Medicine, University of Debrecen, Debrecen, Hungary.|MTA-DE Vascular Biology, Thrombosis and Hemostasis Research Group, Hungarian Academy of Sciences, Debrecen, Hungary.
Viktória
V
Jeney
Faculty of Medicine, Division of Nephrology, Department of Internal Medicine, University of Debrecen, Debrecen, Hungary.|MTA-DE Vascular Biology, Thrombosis and Hemostasis Research Group, Hungarian Academy of Sciences, Debrecen, Hungary.
József
J
Balla
Faculty of Medicine, Division of Neonatology, Department of Pediatrics, University of Debrecen, Debrecen, Hungary.
György
G
Balla
D000469:Alkaline Phosphatase / Q000378:metabolism; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D002117:Calcitriol / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000378:metabolism; D004872:Ergocalciferols / Q000378:metabolism; D005293:Ferritins / Q000378:metabolism*; D005994:Glycerophosphates / Q000494:pharmacology; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D015675:Osteocalcin / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism; D013871:Thiones / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D061205:Vascular Calcification / Q000378:metabolism / Q000503:physiopathology
D004872:Ergocalciferols; D005994:Glycerophosphates; D010710:Phosphates; D013871:Thiones; D013876:Thiophenes; D015675:Osteocalcin; D002762:Cholecalciferol; C084656:paricalcitol; D005293:Ferritins; D000469:Alkaline Phosphatase; D002117:Calcitriol; D002118:Calcium; C049325:1,2-dithiol-3-thione; C031463:beta-glycerophosphoric acid
ferritin; ferroxidase activity; vascular calcification; vitamin D3; β-glycerophosphate