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Molecular Medicine

, Volume 19, Issue 1, pp 195–202 | Cite as

Suppression of Coronary Atherosclerosis by Helix B Surface Peptide, a Nonerythropoietic, Tissue-Protective Compound Derived from Erythropoietin

  • Hiroto Ueba
  • Masashi Shiomi
  • Michael Brines
  • Michael Yamin
  • Tsutomu Kobayashi
  • Junya Ako
  • Shin-ichi Momomura
  • Anthony Cerami
  • Masanobu Kawakami
Research Article

Abstract

Erythropoietin (EPO), a type I cytokine originally identified for its critical role in hematopoiesis, has been shown to have non-hematopoietic, tissue-protective effects, including suppression of atherosclerosis. However, prothrombotic effects of EPO hinder its potential clinical use in nonanemic patients. In the present study, we investigated the antiatherosclerotic effects of helix B surface peptide (HBSP), a nonerythropoietic, tissue-protective compound derived from EPO, by using human umbilical vein endothelial cells (HUVECs) and human monocytic THP-1 cells in vitro and Watanabe heritable hyperlipidemic spontaneous myocardial infarction (WHHLMI) rabbits in vivo. In HUVECs, HBSP inhibited apoptosis (≈70%) induced by C-reactive protein (CRP), a direct mediator of atherosclerosis. By using a small interfering RNA approach, Akt was shown to be a key molecule in HBSP-mediated prevention of apoptosis. HBSP also attenuated CRP-induced production of tumor necrosis factor (TNF)-α and matrix metalloproteinase-9 in THP-1 cells. In the WHHLMI rabbit, HBSP significantly suppressed progression of coronary atherosclerotic lesions as assessed by mean cross-sectional stenosis (HBSP 21.3 ± 2.2% versus control peptide 38.0 ± 2.7%) and inhibited coronary artery endothelial cell apoptosis with increased activation of Akt. Furthermore, TNF-α expression and the number of M1 macrophages and M1/M2 macrophage ratio in coronary atherosclerotic lesions were markedly reduced in HBSP-treated animals. In conclusion, these data demonstrate that HBSP suppresses coronary atherosclerosis, in part by inhibiting endothelial cell apoptosis through activation of Akt and in association with decreased TNF-α production and modified macrophage polarization in coronary atherosclerotic lesions. Because HBSP does not have the prothrombotic effects of EPO, our study may provide a novel therapeutic strategy that prevents progression of coronary artery disease.

Notes

Acknowledgments

We thank Takashi Ito, Satoshi Yamada, Nobue Hirayama, Harue Fukaya, Kimiko Aoki, Chie Ishikawa and Kazuko Futaka for expert technical assistance.

This work was funded in part by Grant-in-Aid for Scientific Research 20590887 from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to H Ueba and M Kawakami) and by a Research Grant for Health Science from the Ministry of Health, Labor and Welfare of Japan (to M Kawakami).

Supplementary material

10020_2013_1901195_MOESM1_ESM.pdf (1.5 mb)
Supplementary material, approximately 1.49 MB.

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Authors and Affiliations

  • Hiroto Ueba
    • 1
  • Masashi Shiomi
    • 2
  • Michael Brines
    • 3
  • Michael Yamin
    • 3
  • Tsutomu Kobayashi
    • 2
  • Junya Ako
    • 1
  • Shin-ichi Momomura
    • 1
  • Anthony Cerami
    • 3
  • Masanobu Kawakami
    • 1
  1. 1.Department of Integrated Medicine 1, Saitama Medical CenterJichi Medical UniversitySaitama CityJapan
  2. 2.Institute for Experimental AnimalsKobe University Graduate School of MedicineKobeJapan
  3. 3.Araim PharmaceuticalsOssiningUSA

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