COX2 inhibition reduces aortic valve calcification in vivo.
OBJECTIVE
Calcific aortic valve disease (CAVD) is a significant cause of morbidity and mortality, which affects ≈1% of the US population and is characterized by calcific nodule formation and stenosis of the valve. Klotho-deficient mice were used to study the molecular mechanisms of CAVD as they develop robust aortic valve (AoV) calcification. Through microarray analysis of AoV tissues from klotho-deficient and wild-type mice, increased expression of the gene encoding cyclooxygenase 2 (COX2; Ptgs2) was found. COX2 activity contributes to bone differentiation and homeostasis, thus the contribution of COX2 activity to AoV calcification was assessed.


RESULTS
In klotho-deficient mice, COX2 expression is increased throughout regions of valve calcification and is induced in the valvular interstitial cells before calcification formation. Similarly, COX2 expression is increased in human diseased AoVs. Treatment of cultured porcine aortic valvular interstitial cells with osteogenic media induces bone marker gene expression and calcification in vitro, which is blocked by inhibition of COX2 activity. In vivo, genetic loss of function of COX2 cyclooxygenase activity partially rescues AoV calcification in klotho-deficient mice. Moreover, pharmacological inhibition of COX2 activity in klotho-deficient mice via celecoxib-containing diet reduces AoV calcification and blocks osteogenic gene expression.


CONCLUSIONS
COX2 expression is upregulated in CAVD, and its activity contributes to osteogenic gene induction and valve calcification in vitro and in vivo.
From The Heart Institute, Cincinnati Children's Hospital Medical Center, OH.
Elaine E
EE
Wirrig
From The Heart Institute, Cincinnati Children's Hospital Medical Center, OH.
M Victoria
MV
Gomez
From The Heart Institute, Cincinnati Children's Hospital Medical Center, OH.
Robert B
RB
Hinton
From The Heart Institute, Cincinnati Children's Hospital Medical Center, OH. Katherine.Yutzey@cchmc.org.
Katherine E
KE
Yutzey
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001021:Aortic Valve / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D002114:Calcinosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D016022:Case-Control Studies; D000068579:Celecoxib; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D005966:Glucuronidase / Q000172:deficiency / Q000235:genetics; D006349:Heart Valve Diseases / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D000090265:Klotho Proteins; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008875:Middle Aged; D010012:Osteogenesis / Q000187:drug effects; D017354:Point Mutation; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D034421:Sus scrofa; D015854:Up-Regulation
D015415:Biomarkers; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D005966:Glucuronidase; D000090265:Klotho Proteins; D000068579:Celecoxib
aortic valve, calcification of; cyclooxygenase 2; heart valves