Heat Shock Protein 27 Protects Against Atherogenesis via an Estrogen-Dependent Mechanism: Role of Selective Estrogen Receptor Beta Modulation

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 29; no. 11; pp. 1751 - 1756
• Main Authors: RAYNER, Katey, JIANGFENG SUN, CHEN, Yong-Xiang, MCNULTY, Melissa, SIMARD, Trevor, XIAOLING ZHAO, WELLS, Dominic J, DE BELLEROCHE, Jacqueline, O'BRIEN, Edward R
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA Lippincott Williams & Wilkins 01.11.2009
• Subjects: Analysis of Variance; Animals; Apolipoproteins E - genetics; Apolipoproteins E - metabolism; Associated diseases and complications; Atherosclerosis (general aspects, experimental research); Atherosclerosis - metabolism; Atherosclerosis - prevention & control; Biological and medical sciences; Blood and lymphatic vessels; Blotting, Western; Cardiology. Vascular system; Cells, Cultured; Diabetes. Impaired glucose tolerance; Disease Models, Animal; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Estrogen Receptor beta - metabolism; Female; HSP27 Heat-Shock Proteins - genetics; HSP27 Heat-Shock Proteins - metabolism; Humans; Macrophages - metabolism; Macrophages - physiology; Medical sciences; Mice; Mice, Inbred Strains; Microscopy, Confocal; Organ Size; Ovariectomy; Probability; Uterus - pathology; Shock; receptors; Estrogen; Cardiovascular disease; heat shock; Ovarian hormone; Vascular disease; proteins; Atherosclerosis; Heat shock protein; Sex steroid hormone; athersclerosis; Hormonal receptor
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.109.193656

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. 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. The extracellular release of and atheroprotection provided by HSP27 is estrogen dependent.