Abstract：
We previously demonstrated a positive relation of secretory phospholipase A2 group IIA (sPLA2-IIA) with circulating high-density lipoprotein cholesterol (HDL-C) in patients with coronary artery disease, and sPLA2-IIA increased cholesterol efflux in THP-1 cells through peroxisome proliferator-activated receptor-γ (PPAR-γ)/liver X receptor α/ATP-binding cassette transporter A1 (ABCA1) signaling pathway. The aim of the present study was to examine the role of sPLA2-IIA over-expression on lipid profile in a transgenic mouse model. Fifteen apoE-/- and C57BL/7 female mice received bone marrow transplantation from transgenic SPLA2-IIA mice, and treated with specific PPAR-γ inhibitor GW9662. High fat diet was given after one week of bone marrow transplantation, and animals were sacrificed after twelve weeks. Immunohistochemical staining showed over-expression of sPLA2-IIA protein in the lung and spleen. The circulating level of HDL-C, but not that of low-density lipoprotein cholesterol (LDL-C), total cholesterol, or total triglyceride, was increased by sPLA2-IIA over-expression, and was subsequently reversed by GW9662 treatment. Over-expression of sPLA2-IIA resulted in augmented expression of cholesterol transporter ABCA1 at mRNA level in the aortas, and at protein level in macrophages, co-localized with macrophage specific antigen CD68. GW9662 exerted potent inhibitory effects on sPLA2-IIA-induced ABCA1 expression. Conclusively, we demonstrated the effects of sPLA2-IIA on circulating HDL-C level and the expression of ABCA1, possibly through regulation of PPAR-γ signaling in transgenic mouse model, that is in concert with the conditions in patients with coronary artery disease.
摘要：
我们先前证明了分泌型磷脂酶A2组IIA（sPLA2-IIA）与冠状动脉疾病患者的循环高密度脂蛋白胆固醇（HDL-C）呈正相关。sPLA2-IIA通过过氧化物酶体增殖物激活受体-γ(PPAR-γ)/肝X受体α/ATP结合盒转运体A1(ABCA1)信号通路增加THP-1细胞胆固醇流出。本研究的目的是研究sPLA2-IIA过表达对转基因小鼠模型中脂质分布的作用。15只apoE-/-和C57BL/7雌性小鼠接受了转基因SPLA2-IIA小鼠的骨髓移植，并用特异性PPAR-γ抑制剂GW9662治疗。骨髓移植一周后给予高脂饮食，12周后处死动物。免疫组织化学染色显示sPLA2-IIA蛋白在肺和脾脏中过度表达。HDL-C的循环水平，但不是低密度脂蛋白胆固醇（LDL-C），总胆固醇,或总甘油三酯，sPLA2-IIA过表达增加，随后被GW9662治疗逆转。sPLA2-IIA的过度表达导致主动脉中胆固醇转运体ABCA1mRNA水平的表达增加,在巨噬细胞的蛋白质水平上，与巨噬细胞特异性抗原CD68共定位。GW9662对sPLA2-IIA诱导的ABCA1表达具有有效的抑制作用。最后，我们证明了sPLA2-IIA对循环HDL-C水平和ABCA1表达的影响，可能是通过调节PPAR-γ信号在转基因小鼠模型中，这与冠状动脉疾病患者的病情一致。
