Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Public Health, Department of Cardiology, Qilu Hospital of Shandong University, Ji'nan 250012, PR China.
Atherosclerosis. 2013 Jun;228(2):370-9. doi: 10.1016/j.atherosclerosis.2013.03.023. Epub 2013 Apr 10.
Although lipoprotein-associated phospholipase A2 (Lp-PLA2) has been regarded as a biomarker and a causative agent for acute coronary events recently, the mechanism of the regulation of Lp-PLA2 has not been fully elucidated yet. This study was aimed to investigate the influence of serum amyloid A (SAA) on the expression of Lp-PLA2 in THP-1 cells and ApoE-deficient (ApoE(-/-)) mice.
THP-1 cells were stimulated by SAA and the mRNA and protein expression of Lp-PLA2 was detected. ApoE(-/-) mice were intravenously injected with murine SAA1 lentivirus. Formyl peptide receptor like-1 (FPRL1) agonist (WKYMVm) and inhibitor (WRW(4)), mitogen-activated protein kinases (MAPKs) inhibitors, and peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist and inhibitor were used to investigate the mechanism of regulation of Lp-PLA2.
Recombinant SAA up-regulated Lp-PLA2 expression in a dose and time-dependent manner in THP-1 cells. Immunohistochemical analysis of aortic root of ApoE(-/-) mice also demonstrated that the expression of Lp-PLA2 was up-regulated significantly with SAA treatment. WRW(4) decreased SAA-induced Lp-PLA2 production; while WKYMVm could induce Lp-PLA2 expression. ERK1/2, JNK1/2, and p38 inhibition reduced SAA-induced Lp-PLA2 production. Furthermore, the results suggested the activation of PPAR-γ played a crucial role in this process.
These results demonstrate that SAA up-regulates Lp-PLA2 production significantly via a FPRL1/MAPKs./PPAR-γ signaling pathway.
尽管脂蛋白相关磷脂酶 A2（Lp-PLA2）最近被认为是急性冠状动脉事件的生物标志物和致病因子，但 Lp-PLA2 的调节机制尚未完全阐明。本研究旨在探讨血清淀粉样蛋白 A（SAA）对 THP-1 细胞和载脂蛋白 E 缺陷（ApoE（-/-））小鼠 Lp-PLA2 表达的影响。
用 SAA 刺激 THP-1 细胞，检测 Lp-PLA2 的 mRNA 和蛋白表达。用鼠 SAA1 慢病毒静脉注射 ApoE（-/-）小鼠。用 FPRL1 激动剂（WKYMVm）和抑制剂（WRW（4））、丝裂原活化蛋白激酶（MAPKs）抑制剂以及过氧化物酶体增殖物激活受体-γ（PPAR-γ）激动剂和抑制剂来研究 Lp-PLA2 调节的机制。
重组 SAA 以剂量和时间依赖的方式在上皮 THP-1 细胞中上调 Lp-PLA2 的表达。ApoE（-/-）小鼠主动脉根部免疫组化分析也表明，SAA 处理后 Lp-PLA2 的表达显著上调。WRW（4）降低 SAA 诱导的 Lp-PLA2 产生；而 WKYMVm 可以诱导 Lp-PLA2 表达。ERK1/2、JNK1/2 和 p38 的抑制减少了 SAA 诱导的 Lp-PLA2 产生。此外，结果表明 PPAR-γ 的激活在这一过程中起着关键作用。
这些结果表明，SAA 通过 FPRL1/MAPKs/PPAR-γ 信号通路显著上调 Lp-PLA2 的产生。
