The Expression of Groups IIE and V Phospholipase A₂ is Associated with an Increased Expression of Osteogenic Molecules in Human Calcified Aortic Valves

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Aim: Eicosanoids play various pathogenic roles in aortic valve calcification. Eicosanoids are derived from the arachidonic acid generated by phospholipase A₂ (PLA₂). We therefore sought to determine whether PLA₂s are expressed in human aortic valves and, if so, whether the expression of PLA₂s is related to the expression of osteogenic molecules in these tissues.
Methods: 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.
Results: Among the PLA₂s examined, the degree of immunoreactivity for PLA₂s-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 PLA₂s-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 PLA₂ in the arachidonic acid cascade, was co-localized with that for PLA₂s-IIE and -V in cells expressing α-smooth muscle actin and macrophages expressing CD68. Furthermore, in the in vitro experiments using cultured VICs, the mRNA expression levels of BMP-2, osteopontin and ALP were suppressed by the inhibition of the expression of PLA₂s-IIE or -V with specific siRNAs.
Conclusions: The expression of PLA₂s-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 PLA₂s-IIE and -V suppresses the induction of osteogenic molecules in cultured cells. Therefore, PLA₂s-IIE and -V may play a role in the pathogenesis of valve calcification.