Serum amyloid A stimulates lipoprotein-associated phospholipase A2 expression in vitro and in vivo

Atherosclerosis. 2013 Jun;228(2):370-9. doi: 10.1016/j.atherosclerosis.2013.03.023. Epub 2013 Apr 10.

Abstract

Objectives: 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.

Methods: 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.

Results: 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.

Conclusion: These results demonstrate that SAA up-regulates Lp-PLA2 production significantly via a FPRL1/MAPKs./PPAR-γ signaling pathway.

MeSH terms

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / biosynthesis*
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / genetics
  • Animals
  • Aorta / drug effects
  • Aorta / enzymology*
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / genetics
  • Enzyme Induction
  • Genetic Vectors
  • Humans
  • Immunohistochemistry
  • Lentivirus / genetics
  • Macrophages / drug effects
  • Macrophages / enzymology*
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism
  • PPAR gamma / agonists
  • PPAR gamma / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • RNA, Messenger / biosynthesis
  • Receptors, Formyl Peptide / agonists
  • Receptors, Formyl Peptide / metabolism
  • Receptors, Lipoxin / agonists
  • Receptors, Lipoxin / metabolism
  • Recombinant Proteins / metabolism
  • Serum Amyloid A Protein / genetics
  • Serum Amyloid A Protein / metabolism*
  • Signal Transduction
  • Time Factors
  • U937 Cells

Substances

  • Apolipoproteins E
  • FPR2 protein, human
  • PPAR gamma
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • Receptors, Formyl Peptide
  • Receptors, Lipoxin
  • Recombinant Proteins
  • SAA1 protein, human
  • Saa2 protein, mouse
  • Serum Amyloid A Protein
  • Mitogen-Activated Protein Kinases
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase