Heat shock protein 27 protects against atherogenesis via an estrogen-dependent mechanism: role of selective estrogen receptor beta modulation.
OBJECTIVE
We recently identified HSP27 as an atheroprotective protein that acts extracellularly to prevent foam cell formation and atherogenesis in female but not male mice, where serum levels of HSP27 were increased and inversely correlated with degree of lesion burden. In the current study we sought to determine whether estrogens are required for the observed atheroprotective benefits of HSP27 as well as its extracellular release.


RESULTS
In vitro estrogens prompted the release of HSP27 from macrophages in an ERbeta specific manner that involved exosomal trafficking. Ovariectomy nullified the previously recognized attenuation in aortic lesion area in HSP27(o/e)apoE(-/-) mice compared to apoE(-/-) mice. Supplementation with 17beta-estradiol resulted in a >15x increase in uterine weight and attenuation of atherogenesis in all mice, although HSP27(o/e)apoE(-/-) had 34% less lesion burden compared to apoE(-/-) mice. Mice treated with the ERbeta-specific agonist, DPN had no effect on uterine weight but a 28% decrease in aortic lesion area in HSP27(o/e)apoE(-/-) compared to apoE(-/-) mice. HSP27 serum levels showed a similar gradual increase with E2 and DPN replacement treatment but did not change in untreated mice.


CONCLUSIONS
The extracellular release of and atheroprotection provided by HSP27 is estrogen dependent.
Rayner
Katey
K
Vascular Biology Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
Sun
Jiangfeng
J
Chen
Yong-Xiang
YX
McNulty
Melissa
M
Simard
Trevor
T
Zhao
Xiaoling
X
Wells
Dominic J
DJ
de Belleroche
Jacqueline
J
O'Brien
Edward R
ER
D000704:Analysis of Variance; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism* / Q000517:prevention & control*; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D047629:Estrogen Receptor beta / Q000378:metabolism*; D005260:Female; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D018613:Microscopy, Confocal; D018832:Molecular Chaperones; D009929:Organ Size; D010052:Ovariectomy; D011336:Probability; D014599:Uterus / Q000473:pathology
D001057:Apolipoproteins E; D047629:Estrogen Receptor beta; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones