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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1751.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Heat Shock Protein 27 Protects Against Atherogenesis via an Estrogen-Dependent Mechanism

Role of Selective Estrogen Receptor Beta Modulation

Katey Rayner; Jiangfeng Sun; Yong-Xiang Chen; Melissa McNulty; Trevor Simard; Xiaoling Zhao; Dominic J. Wells; Jacqueline de Belleroche; Edward R. O'Brien

From the Vascular Biology Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada (K.R., J.S., Y.-X.C., M.N., T.S., X.Z., E.R.O’B.); and Imperial College, London, UK (D.J.W., J.deB.).

Correspondence to Dr Edward O’Brien, Vascular Biology Laboratory, Professor, Division of Cardiology, Room H-2263, University of Ottawa Heart Institute, Ottawa, Ontario, Canada K1Y4W7. E-mail eobrien{at}ottawaheart.ca

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.

Methods and Results— In vitro estrogens prompted the release of HSP27 from macrophages in an ERβ specific manner that involved exosomal trafficking. Ovariectomy nullified the previously recognized attenuation in aortic lesion area in HSP27^o/eapoE^–/– mice compared to apoE^–/– mice. Supplementation with 17β-estradiol resulted in a >15x increase in uterine weight and attenuation of atherogenesis in all mice, although HSP27^o/eapoE^–/– had 34% less lesion burden compared to apoE^–/– mice. Mice treated with the ERβ-specific agonist, DPN had no effect on uterine weight but a 28% decrease in aortic lesion area in HSP27^o/eapoE^–/– 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.

Heat shock protein 27 has previously been shown to be atheroprotective in a mouse model of atherosclerosis, but only in females. We now report that both the atheroprotective effects and the release of HSP27 into the serum are dependent on estrogen, and can be stimulated using a specific estrogen-receptor β modulator.

Key Words: heat shock • proteins • estrogen • receptors • athersclerosis