Modulation of estrogen signaling by the novel interaction of heat shock protein 27, a biomarker for atherosclerosis, and estrogen receptor beta: mechanistic insight into the vascular effects of estrogens.

OBJECTIVE: We sought to discover proteins that associate with estrogen receptor beta (ERbeta) and modulate estrogen signaling. METHODS AND RESULT: Using a yeast 2-hybrid screen, we identified heat shock protein 27 (HSP27) as an ERbeta-associated protein. HSP27 is a recently identified biomarker of atherosclerosis that is secreted at reduced levels from atherosclerotic compared with normal arteries. In vitro protein-binding assays confirmed the specific interaction of HSP27 with ERbeta and not ERalpha. HSP27 expression was absent in coronary arteries with complex atherosclerotic lesions. Interestingly, HSP27 expression was also absent in 60% of coronary arteries from young males and females (27+/-6.5 years) with normal histology or nonobstructive fatty streaks/atheromas. Moreover, the absence of HSP27 in these normal or minimally diseased arteries coincided with the loss of ERbeta expression. Only 35% of arteries showed coexpression of HSP27 and ERbeta. Relative to controls, estradiol-mediated transcription was reduced 20% with overexpression of HSP27 and increased 44% when HSP27 protein levels were reduced with HSP27 siRNA.
CONCLUSIONS: HSP27, an ERbeta-associated protein, shows attenuated expression with coronary atherosclerosis and modulates estrogen signaling.