The Expression of Groups IIE and V Phospholipase A<sub>2</sub> is Associated with an Increased Expression of Osteogenic Molecules in Human Calcified Aortic Valves
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<b><i>Aim</i></b>: Eicosanoids play various pathogenic roles in aortic valve calcification. Eicosanoids are derived from the arachidonic acid generated by phospholipase A<sub>2</sub> (PLA<sub>2</sub>). We therefore sought to determine whether PLA<sub>2s</sub> are expressed in human aortic valves and, if so, whether the expression of PLA<sub>2s</sub> is related to the expression of osteogenic molecules in these tissues.<br><b><i>Methods</i></b>: Histological and gene expression analyses of 38 non-rheumatic aortic valves obtained at the time of cardiac valve replacement surgery were conducted. Moreover, gene expression analyses were performed using valve interstitial cells (VICs) obtained from human aortic valves.<br><b><i>Results</i></b>: Among the PLA<sub>2s</sub> examined, the degree of immunoreactivity for PLA<sub>2s</sub>-IIE and -V was found to significantly correlate with the grade of calcification in the aortic valves. The degree of immunoreactivity and gene expression levels of PLA<sub>2s</sub>-IIE and -V significantly correlated with those of bone morphogenetic protein (BMP)-2, osteopontin and alkaline phosphatase (ALP). In addition, immunoreactivity for cyclooxygenase (COX)-1, COX-2 and 5-lipoxygenase, downstream enzymes of PLA<sub>2</sub> in the arachidonic acid cascade, was co-localized with that for PLA<sub>2s</sub>-IIE and -V in cells expressing <i>α</i>-smooth muscle actin and macrophages expressing CD68. Furthermore, in the <i>in vitro</i> experiments using cultured VICs, the mRNA expression levels of BMP-2, osteopontin and ALP were suppressed by the inhibition of the expression of PLA<sub>2s</sub>-IIE or -V with specific siRNAs.<br><b><i>Conclusions</i></b>: The expression of PLA<sub>2s</sub>-IIE and -V correlates with the development of calcification as well as the expression of pro-osteogenic molecules in human aortic valves, and inhibiting the expression of PLA<sub>2s</sub>-IIE and -V suppresses the induction of osteogenic molecules in cultured cells. Therefore, PLA<sub>2s</sub>-IIE and -V may play a role in the pathogenesis of valve calcification.
- Journal of Atherosclerosis and Thrombosis
Journal of Atherosclerosis and Thrombosis 21(12), 1308-1325, 2014
Japan Atherosclerosis Society