Heat shock protein-27 attenuates foam cell formation and atherogenesis by down-regulating scavenger receptor-A expression via NF-κB signaling.
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-κB) signaling (p<0.001 versus control), while an inhibitor of NF-κB 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 3weeks 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-κB signaling. Lastly, SR-A is required for HSP27-mediated atheroprotection in vivo.
University of Ottawa Heart Institute, Ottawa, Canada.
Joshua E
JE
Raizman
Yong-Xiang
YX
Chen
Tara
T
Seibert
Benjamin
B
Hibbert
Charles M
CM
Cuerrier
Samira
S
Salari
Xiaoling
X
Zhao
Tieqiang
T
Hu
Chunhua
C
Shi
Xiaoli
X
Ma
Trevor
T
Simard
Justin
J
Caravaggio
Katey
K
Rayner
Dawn
D
Bowdish
Kathryn
K
Moore
Edward R
ER
O'Brien
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016466:CHO Cells; D002460:Cell Line; D003412:Cricetulus; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005260:Female; D005487:Foam Cells / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000494:pharmacology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D051117:Scavenger Receptors, Class A / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013450:Sulfones / Q000494:pharmacology
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D001057:Apolipoproteins E; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C486113:Hsbp1 protein, mouse; C486699:Hspb2 protein, mouse; D018832:Molecular Chaperones; D016328:NF-kappa B; D009363:Neoplasm Proteins; D009570:Nitriles; D051117:Scavenger Receptors, Class A; D013450:Sulfones
Atherosclerosis; Heat shock protein 27; Macrophage; NF-κB; Scavenger receptor-A