A novel role of the sympatho-adrenergic system in regulating valve calcification.
BACKGROUND
Aortic valve calcification is a progressive process resembling ossification. Recent evidence indicates that the sympathetic nervous system plays an important role in regulating bone deposition and resorption through the beta2-adrenergic receptors (beta2-ARs). The aim of this study is to determine the level and pattern of expression of beta2-ARs in human valve interstitial cells (ICs) and assess their influence on differentiation of the cells into an osteoblast-like phenotype.


RESULTS
Immunohistochemical analysis demonstrated a high expression of beta2-ARs, beta1-ARs, beta3-AR,s and receptor activator of nuclear factor-kappaB (RANK) in calcified aortic valves. The expression of beta2-ARs and beta1-ARs mRNA was assessed by real-time TaqMan PCR in cultures of human aortic valve ICs. Human valve ICs treated with the selective beta2-AR agonist, salmeterol, in the presence of osteogenic medium showed a significant 5-fold decrease in the alkaline phosphatase (ALP) activity in comparison to cells treated with osteogenic medium only (P<0.05). Immunocytochemical staining of the valve ICs showed a concomitant reduction in osteocalcin expression. In addition, other beta2-AR agonists caused a reduction in the protein expression of bone markers including ALP, Cbfa-1, and periostin. Human valve ICs treated with norepinephrine, in the presence of osteogenic medium, did not show a significant reduction in the ALP activity.


CONCLUSIONS
These findings suggest an important role of the beta2-ARs in regulating valve calcification and may identify potential therapeutic targets.
Osman
Lana
L
Imperial College London, Heart Science Centre, Department of Cardiothoracic Surgery, Royal Brompton and Harefield NHS Trust, Harefield, Middlesex, UK.
Chester
Adrian H
AH
Sarathchandra
Padmini
P
Latif
Najma
N
Meng
Wenfang
W
Taylor
Patricia M
PM
Yacoub
Magdi H
MH
D000293:Adolescent; D000318:Adrenergic beta-Agonists / Q000494:pharmacology / Q000627:therapeutic use; D000368:Aged; D001021:Aortic Valve / Q000187:drug effects / Q000473:pathology* / Q000502:physiology*; D002114:Calcinosis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D002648:Child; D006801:Humans; D008875:Middle Aged; D011943:Receptors, Adrenergic, beta / Q000502:physiology*
D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta