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Molecular Medicine

, Volume 17, Issue 9–10, pp 1065–1074 | Cite as

BRAP Activates Inflammatory Cascades and Increases the Risk for Carotid Atherosclerosis

  • Yi-Chu Liao
  • Yung-Song Wang
  • Yuh-Cherng Guo
  • Kouichi Ozaki
  • Toshihiro Tanaka
  • Hsiu-Fen Lin
  • Ming-Hong Chang
  • Ku-Chung Chen
  • Ming-Lung Yu
  • Sheng-Hsiung Sheu
  • Suh-Hang Hank Juo
Research Article

Abstract

The BRCA-1 associated protein gene (BRAP) was recently identified as a susceptibility gene for myocardial infarction (MI). In the present study we aimed to decipher the association between the BRAP polymorphism and carotid atherosclerosis and the mechanism underlying its proatherogenic effect. A total of 1749 stroke/MI-free volunteers received carotid ultrasonic examinations for the measurement of intima-medial thickness (IMT) and plaque. The promoter polymorphism rs11066001 was selected because it affects the transcription of BRAP. We found that the GG genotype was associated with a 1.58-fold increased risk for having at least one plaque compared to carrying the A allele (P = 0.021). When subjects were divided by the cutoff value of IMT above the mean plus 1 standard deviation, there was an overrepresentation of the GG genotype in the subjects with thicker IMT (P = 0.004). The expression of BRAP increased significantly when human aortic smooth muscle cells (HASMCs) were treated with lipopolysaccharide (LPS). HASMCs were transfected with small interfering RNA against BRAP or scrambled sequences before treatment with LPS. Knockdown of BRAP led to attenuated HASMC proliferation and reduced secretion of monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) in response to LPS. Downregulation of BRAP did not affect the protein levels of nuclear factor-κB (NF-κB), but prohibited its nuclear translocation. Coimmunoprecipitation experiments confirmed an interaction between BRAP and the two major components of the IKK signalosome, IκBβ and IKKβ. Collectively, BRAP conferred a risk for carotid plaque and IMT. Inflammatory stimuli upregulated BRAP expression, and BRAP activated inflammatory cascades by regulating NF-κB nuclear translocation.

Notes

Acknowledgments

This work was supported by grants from the following organizations: National Health Research Institutes, Taiwan (NHRI-Ex96-9607PI); National Science Council, Taiwan (NSC 97-2314-B-037-019, NSC 98-2314-B-037-048, NSC97-2314-B-037-043-MY2); Kaohsiung Medical University intramural grant (KMUH98-8I11); Kaohsiung Municipal Hsiao-Kang Hospital (KMHKH-96-027); Taichung Veterans General Hospital (TCVGH-983403C and TCVGH-993402C); and the Naito Foundation, Mitsubishi Foundation, and Tokyo Biochemical Research Foundation (Japan).

Supplementary material

10020_2011_1791065_MOESM1_ESM.pdf (419 kb)
BRAP Activates Inflammatory Cascades and Increases the Risk for Carotid Atherosclerosis

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Copyright information

© The Feinstein Institute for Medical Research 2011
www.feinsteininstitute.org

Authors and Affiliations

  • Yi-Chu Liao
    • 1
    • 5
    • 6
  • Yung-Song Wang
    • 2
  • Yuh-Cherng Guo
    • 3
    • 12
  • Kouichi Ozaki
    • 7
  • Toshihiro Tanaka
    • 7
  • Hsiu-Fen Lin
    • 3
    • 8
  • Ming-Hong Chang
    • 5
    • 6
  • Ku-Chung Chen
    • 2
  • Ming-Lung Yu
    • 4
    • 11
  • Sheng-Hsiung Sheu
    • 4
    • 10
  • Suh-Hang Hank Juo
    • 2
    • 9
  1. 1.Graduate Institute of Medicine, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan
  2. 2.Department of Medical Genetics, College of MedicineKaohsiung Medical UniversityKaohsiung CityTaiwan
  3. 3.Department of Neurology, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan
  4. 4.Department of Internal Medicine, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan
  5. 5.Section of NeurologyTaichung Veterans General HospitalTaichungTaiwan
  6. 6.Department of NeurologyNational Yang-Ming University, School of MedicineTaipeiTaiwan
  7. 7.Laboratory for Cardiovascular Diseases, Center for Genomic MedicineRIKENYokohamaJapan
  8. 8.Department of NeurologyKaohsiung Medical University HospitalKaohsiungTaiwan
  9. 9.Department of Medical ResearchKaohsiung Medical University HospitalKaohsiungTaiwan
  10. 10.Division of Cardiology, Department of Internal MedicineKaohsiung Medical University HospitalKaohsiungTaiwan
  11. 11.Department of Internal MedicineKaohsiung Municipal Ta-Tung HospitalKaohsiungTaiwan
  12. 12.Department of NeurologyKaohsiung Municipal Hsiao-Kang HospitalKaohsiungTaiwan

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