Journal of Molecular Medicine

, Volume 92, Issue 5, pp 509–521 | Cite as

A novel gene regulator, pyrrole–imidazole polyamide targeting ABCA1 gene increases cholesterol efflux from macrophages and plasma HDL concentration

  • Akiko Tsunemi
  • Takahiro Ueno
  • Noboru Fukuda
  • Takayoshi Watanabe
  • Kazunobu Tahira
  • Akira Haketa
  • Yoshinari Hatanaka
  • Sho Tanaka
  • Taro Matsumoto
  • Yoshiaki Matsumoto
  • Hiroki Nagase
  • Masayoshi Soma
Original Article


Pyrrole–imidazole (PI) polyamides are nuclease-resistant novel compounds that inhibit transcription factors by binding to the minor groove of DNA. A PI polyamide that targets mouse ABCA1 and increases ABCA1 gene expression was designed and evaluated as an agent to increase plasma HDL concentration. A PI polyamide was designed to bind the activator protein-2 binding site of the mouse ABCA1 promoter. The effect of this PI polyamide on ABCA1 expression was evaluated by real-time RT-PCR and Western blotting using RAW264 cells. In vivo effects of this polyamide on ABCA1 gene expression and plasma HDL level were examined in C57B6 mice. One milligram per kilogram of body weight of PI polyamide was injected via the tail veins every 2 days for 1 week, and plasma lipid profiles were evaluated. PI polyamide showed a specific binding to the target DNA in gel mobility shift assay. Treatment of RAW264 cells with 1.0 μM PI polyamide significantly increased ABCA1 mRNA expression. PI polyamide also significantly increased apolipoprotein AI-mediated HDL biogenesis in RAW264 cells. Cellular cholesterol efflux mediated by apolipoprotein AI was significantly increased by the PI polyamide treatment. PI polyamide significantly increased expression of ABCA1 mRNA in the liver of C57B6 mice. Plasma HDL concentration was increased by PI polyamide administration. All of the HDL sub-fractions showed a tendency to increase after PI polyamide administration. The designed PI polyamide that targeted ABCA1 successfully increased ABCA1 expression and HDL biogenesis. This novel gene-regulating agent is promising as a useful compound to increase plasma HDL concentration.

Key messages

  • A novel pyrrole–imidazole (PI) polyamide binds to ABCA1.

  • PI polyamide interfered with binding of AP-2ɑ protein to the ABCA1 gene promoter.

  • PI polyamide inhibited the AP-2ɑ-mediated reduction of ABCA1 gene and protein expression.

  • PI polyamide increased ABCA1 protein and apolipoprotein AI mediated HDL biogenesis.

  • PI polyamide is a new gene regulator for the prevention of atherosclerotic diseases.


ABCA1 PI polyamide HDL AP-2 



This work was partially supported by a grant from the “Strategic Research Base Development” Program for Private Universities subsidized by MEXT (2011).

Conflict of interest

There is no conflict of interest to disclose for any of the authors.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Akiko Tsunemi
    • 1
  • Takahiro Ueno
    • 1
    • 2
  • Noboru Fukuda
    • 1
  • Takayoshi Watanabe
    • 3
  • Kazunobu Tahira
    • 1
  • Akira Haketa
    • 1
  • Yoshinari Hatanaka
    • 1
  • Sho Tanaka
    • 1
  • Taro Matsumoto
    • 4
  • Yoshiaki Matsumoto
    • 5
  • Hiroki Nagase
    • 3
  • Masayoshi Soma
    • 1
    • 2
    • 6
  1. 1.Department of Medicine, Division of Nephrology, Hypertension and EndocrinologyNihon University School of MedicineItabashiJapan
  2. 2.Innovative Therapy Research Group, Nihon University Research Institute of Medical ScienceNihon University School of MedicineItabashiJapan
  3. 3.Chiba Cancer Center Research InstituteChuoJapan
  4. 4.Department of Functional Morphology, Division of Cell Regeneration and TransplantationNihon University School of MedicineItabasiJapan
  5. 5.Department of Clinical Pharmacokinetics, College of PharmacyNihon UniversityFunabashiJapan
  6. 6.Department of Medicine, Division of General MedicineNihon University School of MedicineItabashiJapan

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