A Novel Role of the Sympatho-Adrenergic System in Regulating Valve Calcification

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Abstract
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 β2-adrenergic receptors (β2-ARs). The aim of this study is to determine the level and pattern of expression of β2-ARs in human valve interstitial cells (ICs) and assess their influence on differentiation of the cells into an osteoblast-like phenotype.Methods and Results—Immunohistochemical analysis demonstrated a high expression of β2-ARs, β1-ARs, β3-AR,s and receptor activator of nuclear factor-κB (RANK) in calcified aortic valves. The expression of β2-ARs and β1-ARs mRNA was assessed by real-time TaqMan PCR in cultures of human aortic valve ICs. Human valve ICs treated with the selective β2-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 (P2-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 β2-ARs in regulating valve calcification and may identify potential therapeutic targets.