A novel role of extracellular nucleotides in valve calcification: a potential target for atorvastatin.
BACKGROUND
Calcific aortic valve disease is a common condition and is associated with inflammatory changes and expression of osteoblast-like cell phenotypes, but the cellular mechanisms are unclear. Recent studies identified extracellular ATP and P2Y receptor cascade as important regulators of bone remodeling, whereas its breakdown product, adenosine, is known to have anti-inflammatory properties. We hypothesize that extracellular ATP and adenosine have important roles in regulating osteoblast differentiation in human valve interstitial cells, and that this can be a potential target for therapy. Method and Results- Primary cultures of human valve interstitial cells (ICs) treated for 21 days with osteogenic media, ATP, and ATP-gamma-S (a stable agonist of the P2Y receptor) revealed a significant increase in alkaline phosphatase (ALP) (an osteoblast marker) activity and expression as measured using spectrophotometric assay and immunocytochemistry staining. Valve ICs treated with adenosine alone did not cause an increase in ALP activity; however, adenosine treatment decreased the ALP activity and expression induced by osteogenic media after 21 days of incubation. In addition, atorvastatin inhibited the activity of ALP induced by ATP in human valve ICs, and enzyme studies revealed that atorvastatin upregulated the breakdown of extracellular ATP into adenosine in human valve ICs after 24-hour treatment.


CONCLUSIONS
These findings identify a novel role for extracellular nucleotides in inducing osteoblast differentiation in human valve ICs in vitro and provide a potential therapeutic target for preventing the disease progression.
Osman
Lana
L
Imperial College, Royal Brompton and Harefield National Health Service Trust, Harefield, Middlesex, UK.
Chester
Adrian H
AH
Amrani
Mohamed
M
Yacoub
Magdi H
MH
Smolenski
Ryszard T
RT
D015720:5'-Nucleotidase / Q000032:analysis; D000241:Adenosine / Q000494:pharmacology*; D000251:Adenosine Triphosphatases / Q000032:analysis; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology*; D000368:Aged; D000469:Alkaline Phosphatase / Q000032:analysis; D001021:Aortic Valve / Q000166:cytology / Q000473:pathology*; D001024:Aortic Valve Stenosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D001081:Apyrase / Q000032:analysis; D000069059:Atorvastatin; D015415:Biomarkers; D002114:Calcinosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006538:Heptanoic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008875:Middle Aged; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D018048:Receptors, Purinergic P2 / Q000187:drug effects / Q000502:physiology*; D015290:Second Messenger Systems / Q000187:drug effects
D015415:Biomarkers; D006538:Heptanoic Acids; D011758:Pyrroles; D018048:Receptors, Purinergic P2; C022571:adenosine 5'-O-(3-thiotriphosphate); D000255:Adenosine Triphosphate; D000069059:Atorvastatin; D000469:Alkaline Phosphatase; D015720:5'-Nucleotidase; D000251:Adenosine Triphosphatases; D001081:Apyrase; D000241:Adenosine