期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
卷 1831, 期 12, 页码 1721-1728出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbalip.2013.07.015
关键词
Atherosclerosis; Heat shock protein 27; Macrophage; Scavenger receptor-A; NF-kappa B
资金
- Canadian Institute for Health Research (CIHR) [ISO 110836]
- Heart and Stroke Foundation of Ontario (HSFO) [T7217]
- CIHR Frederick Banting and Charles Best Canada Graduate Doctoral Award
- le Fonds de Recherche en Sante du Quebec (FRSQ)
- University of Ottawa Heart Institute
- CIHR Institute of Gender & Health/Ontario Women's Health Council (IGH/OWHC) Master's Award
- HSFO
- CIHR/IGH/OWHC
Previously, we showed an inverse correlation between HSP27 serum levels and experimental atherogenesis in ApoE(-/-) mice that over-express HSP27 and speculated that the apparent binding of HSP27 to scavenger receptor-A (SR-A) was of mechanistic importance in attenuating foam cell formation. However, the nature and importance of the interplay between HSP27 and SR-A in atheroprotection remained unclear. Treatment of THP-1 macrophages with recombinant HSP27 (rHSP27) inhibited acLDL binding (-34%; p < 0.005) and uptake (-38%, p < 0.05). rHSP27 reduced SR-A mRNA (-39%, p = 0.02), total protein (-56%, p = 0.01) and cell surface (-53%, p < 0.001) expression. The reduction in SR-A expression by rHSP27 was associated with a 4-fold increase in nuclear factor-kappa B (NF-kappa B) signaling (p < 0.001 versus control), while an inhibitor of NF-kappa B signaling, BAY11-7082, attenuated the negative effects of rHSP27 on both SR-A expression and lipid uptake. To determine if SR-A is required for HSP27 mediated atheroprotection in vivo, ApoE(-/-) and ApoE(-/-) SR-A(-/-) mice fed with a high fat diet were treated for 3 weeks with rHSP25. Compared to controls, rHSP25 therapy reduced aortic en face and aortic sinus atherosclerotic lesion size in ApoE(-/-) mice by 39% and 36% (p < 0.05), respectively, but not in ApoE(-/-)SR-A(-/-) mice. In conclusion, rHSP27 diminishes SR-A expression, resulting in attenuated foam cell formation in vitro. Regulation of SR-A by HSP27 may involve the participation of NF-kappa B signaling. Lastly, SR-A is required for HSP27-mediated atheroprotection in vivo. (C) 2013 Elsevier B.V. All rights reserved.
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