Abstract 15857: Aortic Valve Calcification is Reduced by COX2 Inhibition
Circulation(2014)
摘要
Calcific aortic valve disease (CAVD) is a significant cause of morbidity and mortality in the United States and is characterized by calcific nodule formation and stenosis of the valve. The molecular mechanisms underlying valve calcification are poorly understood and surgical replacement remains the most common treatment option for severe aortic stenosis. Molecular mechanisms and treatment strategies for CAVD were examined in klotho-deficient mice, which develop aortic valve (AoV) calcification in association with accelerated aging. Through a microarray screen comparing AoV tissues from klotho-deficient and wild type mice, the gene encoding COX2 (cyclooxygenase 2/ ptgs2) was observed to have significantly increased expression in calcified AoV tissues of klotho-deficient mice. Since COX2 activity contributes to bone differentiation and homeostasis, we hypothesize that COX2 activity also contributes to valve calcification through induction of osteogenic mechanisms. In klotho-deficient mice, COX2 expression is increased throughout regions of valve calcification and is induced in the valvular interstitial cells (VICs) prior to the presence of detectable calcification. Similarly, COX2 expression is increased in human diseased AoVs in regions of valve calcification. Treatment of cultured porcine aortic VICs with osteogenic media induces bone marker gene expression, which is blocked by inhibition of COX2 activity, supporting a therapeutic strategy of COX2 inhibition in CAVD. In vivo, genetic loss of function of COX2 cyclooxygenase activity partially rescues AoV calcification in klotho-deficient mice. Moreover, pharmacologic inhibition of COX2 activity in klotho-deficient mice via celecoxib-containing diet reduces AoV calcification and blocks bone marker gene expression. Thus, COX2 expression is upregulated in CAVD and inhibition of COX2 activity is an effective treatment for reducing AoV calcification in klotho-deficient mice. The data presented show for the first time that COX2 activity contributes to bone marker gene induction and AoV calcification and that COX2 inhibition effectively reduces valve calcification in a mouse model of CAVD.
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关键词
aortic valve calcification
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