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

  • Bo Li
    Affiliations
    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
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  • Zhe Dong
    Affiliations
    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
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  • Hui Liu
    Affiliations
    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
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  • Yan-fei Xia
    Affiliations
    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
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  • Xiao-man Liu
    Affiliations
    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
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  • Bei-bei Luo
    Affiliations
    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
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  • Wen-ke Wang
    Affiliations
    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
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  • Bin Li
    Affiliations
    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
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  • Fei Gao
    Affiliations
    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
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  • Cheng Zhang
    Affiliations
    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
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  • Ming-xiang Zhang
    Affiliations
    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
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  • Yun Zhang
    Affiliations
    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
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  • Feng-shuang An
    Correspondence
    Corresponding author. Qilu Hospital of Shandong University, No. 107, Wen Hua Xi Road, Ji'nan 250012, Shandong, PR China. Tel.: +86 531 82169257; fax: +86 531 86169356.
    Affiliations
    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
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      Highlights

      • Lp-PLA2 is up-regulated by SAA both in THP-1 cells and ApoE−/− mice.
      • FPRL1 is required for SAA-induced Lp-PLA2 production.
      • MAPKs mediate SAA-induced Lp-PLA2 production.
      • PPAR-γ mediates SAA-induced Lp-PLA2 production.

      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 (WRW4), 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. WRW4 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.

      Keywords

      Abbreviations:

      Lp-PLA2 (lipoprotein-associated phospholipase A2), SAA (serum amyloid A), FPRL1 (formyl peptide receptor like-1), GAPDH (glyceraldehydes-3-phosphate dehydrogenase), PPAR-γ (peroxisome proliferator-activated receptor-γ), MAPKs (mitogen-activated protein kinases), JNK (c-Jun N-terminal kinase), ERK1/2 (p44/42 MAP kinase), p38 (p38 mitogen-activated protein kinases), ABCA1 (ATP-binding cassette sub-family A member 1), ABCG1 (ATP-binding cassette sub-family G member 1), WKYMVm (Trp-Lys-Tyr-Met-Val-D-Met), WRW4 (H2N-WRWWWW-CONH2), PD98059 (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one), SP600125 (2H-Dibenzo[cd,g]indazol-6-one), SB203580 (4-[4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-1H-imidazol-5-yl]pyridine), GW9662 (2-Chloro-5-nitro-N-phenylbenzamide)
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