Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development.
Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development.
复制标题
作者：
脂蛋白相关磷脂酶A2 （Lp-PLA2）活性升高与心脏事件风险增加有关，但目前尚不清楚Lp-PLA2是否是致病因子。本研究表明，darapladib选择性抑制Lp-PLA2可减少糖尿病和高胆固醇血症猪晚期冠状动脉粥样硬化的发展。Darapladib显著抑制血浆和病变处Lp-PLA2活性，降低病变处溶血磷脂酰胆碱含量。冠状动脉基因表达分析显示，darapladib具有普遍的抗炎作用，可显著降低巨噬细胞和T淋巴细胞功能相关的24个基因的表达。Darapladib治疗导致斑块面积显著减少，值得注意的是，坏死核心区域和内侧破坏明显减少，导致表型不稳定的病变减少。这些数据表明，选择性抑制Lp-PLA2抑制晚期冠状动脉粥样硬化病变的进展，并证实了独立于高胆固醇血症的血管炎症在涉及心肌梗死和中风发病机制的病变发展中的关键作用。
Increased lipoprotein-associated phospholipase A2 (Lp-PLA2) activity is associated with increased risk of cardiac events, but it is not known whether Lp-PLA2 is a causative agent. Here we show that selective inhibition of Lp-PLA2 with darapladib reduced development of advanced coronary atherosclerosis in diabetic and hypercholesterolemic swine. Darapladib markedly inhibited plasma and lesion Lp-PLA2 activity and reduced lesion lysophosphatidylcholine content. Analysis of coronary gene expression showed that darapladib exerted a general anti-inflammatory action, substantially reducing the expression of 24 genes associated with macrophage and T lymphocyte functioning. Darapladib treatment resulted in a considerable decrease in plaque area and, notably, a markedly reduced necrotic core area and reduced medial destruction, resulting in fewer lesions with an unstable phenotype. These data show that selective inhibition of Lp-PLA2 inhibits progression to advanced coronary atherosclerotic lesions and confirms a crucial role of vascular inflammation independent from hypercholesterolemia in the development of lesions implicated in the pathogenesis of myocardial infarction and stroke.