Laboratoire d'Études Moléculaires des Valvulopathies, Groupe de Recherche en Valvulopathies, Quebec Heart and Lung Institute/Research Center, Department of Surgery, Laval University, Quebec City, Quebec, Canada.
Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec City, Quebec, Canada.
J Am Coll Cardiol. 2014 Feb 11;63(5):460-9. doi: 10.1016/j.jacc.2013.05.105. Epub 2013 Oct 23.
OBJECTIVES: This study sought to document the presence and role of lipoprotein-associated phospholipase A2 (Lp-PLA2) in calcific aortic valve disease (CAVD). BACKGROUND: CAVD is a chronic disorder characterized by pathological mineralization and remodeling. Studies have indicated that human CAVD tissues are infiltrated by lipids and that inflammation may play a role in the pathobiology. We hypothesized that Lp-PLA2 (encoded by the PLA2G7 gene) is expressed in CAVD and may play a role in the mineralization of valve interstitial cells. METHODS: We have documented the expression of the phospholipase A2 family of genes in aortic valves by using a transcriptomic assay. Messenger ribonucleic acid and protein expression were confirmed in aortic valves explanted from 60 patients by quantitative polymerase chain reaction and immunohistochemistry, respectively. The effect of lysophosphatidylcholine, the product of Lp-PLA2 activity, was documented on the mineralization of valve interstitial cell cultures. RESULTS: Transcriptomic analyses of CAVD and control nonmineralized aortic valves revealed that Lp-PLA2 was increased by 4.2-fold in mineralized aortic valves. Higher expression of Lp-PLA2 in stenotic aortic valves was confirmed by quantitative polymerase chain reaction, immunohistochemistry, and enzymatic Lp-PLA2 activity. The number of Lp-PLA2 transcripts correlated with several indexes of tissue remodeling. In vitro, lysophosphatidylcholine increased the expression of alkaline phosphatase, the ectonucleotide pyrophosphatase/phosphodiesterase 1 enzyme, sodium-dependent phosphate cotransporter 1 (encoded by the SLC20A1 gene), and osteopontin. We then showed that lysophosphatidylcholine-induced mineralization involved ectonucleotidase enzyme as well as apoptosis through a protein-kinase-A-dependent pathway. CONCLUSIONS: Together, these results demonstrated that Lp-PLA2 is highly expressed in CAVD, and it plays a role in the mineralization of valve interstitial cells. Further work is necessary to document whether Lp-PLA2 could be considered as a novel target in CAVD.
目的：本研究旨在记录脂蛋白相关磷脂酶 A2（Lp-PLA2）在钙化性主动脉瓣疾病（CAVD）中的存在和作用。
背景：CAVD 是一种以病理性矿化和重塑为特征的慢性疾病。研究表明，人类 CAVD 组织中存在脂质浸润，炎症可能在其病理生物学中发挥作用。我们假设 Lp-PLA2（由 PLA2G7 基因编码）在 CAVD 中表达，并可能在瓣膜间质细胞的矿化中发挥作用。
方法：我们通过转录组学分析记录了主动脉瓣中磷脂酶 A2 家族基因的表达。通过定量聚合酶链反应和免疫组织化学分别确认从 60 例患者中取出的主动脉瓣中的信使核糖核酸和蛋白质表达。记录了 Lp-PLA2 活性产物溶血磷脂酰胆碱对瓣膜间质细胞培养物矿化的影响。
结果：对 CAVD 和非矿化对照主动脉瓣的转录组学分析表明，Lp-PLA2 在矿化主动脉瓣中的表达增加了 4.2 倍。通过定量聚合酶链反应、免疫组织化学和酶 Lp-PLA2 活性进一步证实了 Lp-PLA2 在狭窄主动脉瓣中的高表达。Lp-PLA2 转录物的数量与组织重塑的几个指标相关。在体外，溶血磷脂酰胆碱增加了碱性磷酸酶、外核苷酸焦磷酸酶/磷酸二酯酶 1 酶、钠依赖性磷酸盐共转运蛋白 1（由 SLC20A1 基因编码）和骨桥蛋白的表达。我们随后表明，溶血磷脂酰胆碱诱导的矿化涉及外核苷酸酶酶以及通过蛋白激酶 A 依赖性途径的细胞凋亡。
结论：综上所述，这些结果表明 Lp-PLA2 在 CAVD 中高度表达，并在瓣膜间质细胞的矿化中发挥作用。需要进一步的研究来证明 Lp-PLA2 是否可以被视为 CAVD 的一个新靶点。
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