Calcific aortic valve disease (CAVD) is considered a disease of aging and is characterized by calcific nodule formation, stenosis of the valve, and induction of osteogenic gene expression. The klotho deficient mouse model of premature aging exhibits CAVD evident in calcific lesions in the aortic valve annulus. Klotho deficient mice develop calcification by 6 weeks of age, with minimal immune cell infiltration and increased osteogenic gene expression. Microarray analyses performed on aortic valve tissues of wild type and klotho deficient mice demonstrate that cyclooxygenase 2 (COX2) expression is increased in klotho deficient mice. We hypothesize that increased COX2 expression contributes to aortic valve calcification and that COX2 inhibition prevents osteogenic gene expression in aortic valve interstitial cells (aVICs). In klotho deficient mice, COX2 protein expression is increased throughout regions of valve calcification relative to wild type controls. Prior to the formation of calcified valve lesions, increased COX2 expression is localized to areas at risk of developing calcification in klotho deficient mice. Thus increased COX2 expression precedes valve calcification. In human explanted calcific aortic valves, COX2 expression also is increased in mineralized regions compared to controls. In bone, COX2 deficiency inhibits osteogenic gene induction. The ability of COX2 inhibition to block osteogenic gene expression was examined using porcine aVICs. Treatment of aVICs with osteogenic media induces bone markers, including osteocalcin, in addition to increasing COX2 gene expression. Furthermore, inhibition of COX2 activity in cells cultured under osteogenic conditions results in significantly decreased expression of osteogenic genes compared to controls. In vivo studies in progress provide initial evidence that loss of COX2 activity reduces aortic valve calcification in klotho deficient mice. In conclusion, COX2 expression is increased in regions of aortic valve calcification in both human and mouse CAVD tissues, and COX2 inhibition suppresses osteogenic gene expression in cultured aVICs. Targeting COX2 enzyme activity may be a potential therapeutic option for preventing or reducing aortic valve calcification in the future.
Artificial Intelligence Models Reveal Sex-Specific Gene Expression in Aortic Valve Calcification
