The OBrien laboratory recently demonstrated that the expression of Heat Shock Protein 27 (HSP27) is reduced in human coronary arteries with atherosclerosis.Moreover,we showed that over-expression of HSP27 is protective against the development of atherosclerosis in mice with a preferential advantage for females-thereby suggesting an estrogen-mediated phenomenon.Indeed,female mice had 10-fold higher serum HSP27 levels compared to males and serum HSP27 levels inversely correlated to aortic lesion area.More recently,we demonstrated that estrogens (particularly ERβ specific agonists) induce the cellular release of HSP27-an effect that can be blocked with the non-selective estrogen receptor antagonist ICI 182,780.In vivo female HSP27 over-expressing atherosclerosis prone mice subjected to ovariectomy were no longer protected against the development of atherosclerosis.However,replacement hormonal therapy with estradiol boosted serum HSP27 levels and was associated with the restoration of atheroprotection.Taken together,these data indicate that estrogens,particularly ERβ specific modulators,release atheroprotective HSP27 into the extracellular space where it can act to reduce the development of atherosclerosis.Studies using estrogen receptor specific modulators as well as recombinant HSP27 to reduce experimental atherosclerosis are ongoing.