Estrogen Receptor Beta and Atherogenesis: Role of Receptor Related Proteins NM23-H2 and HSP27

There exists an obvious gender disparity in the incidence of cardiovascular disease, with more women over the age of 60 years dying each year compared to their male counterparts. However, pre-menopausal women appear to be spared from developing this disease. Naturally occurring female hormones such as estrogen are thought to provide the cardiovascular system with some form of protection from atherosclerosis. However, the mechanisms behind this protection are poorly understood, and large clinical trials failed to demonstrate any significant cardiovascular benefit for women receiving hormone replacement therapy. Estrogen acts through two primary receptors, ERalpha and ERbeta, and evidence is emerging to suggest that ERbeta is a key mediator of estrogen action in the vessel wall. The objective of this doctoral thesis was to understand more about ERbeta in atherosclerosis by elucidating novel molecular mechanisms of ERbeta action. Two novel proteins were discovered to interact with ERbeta in the vessel wall: (i) non-metastatic protein-23 (NM23-H2) and (ii) heat shock protein 27 (HSP27). The first portion of this study demonstrated that NM23-H2 and ERbeta interact in vascular cells in vitro and NM23-H2 can act as a modest co-activator of estrogen-mediated transcriptional signaling via ERbeta. The expression of NM23-H2 is diminished with progression of atherosclerosis in human coronary arteries, indicating that with advancing disease, the regulation of important estrogen and ERbeta-mediated events may be impaired. The second portion of this study showed that over-expression of HSP27 in a mouse model of atherosclerosis can protect from the development of atherosclerotic lesions, but is dependent on the presence of estrogen. HSP27 release from macrophages is induced by estrogen, where it may serve to protect against atherosclerosis by binding the scavenger receptor-A and preventing the uptake of atherogenic lipoproteins and the ensuing inflammation. The release of this atheroprotective HSP27 is mediated preferentially by ERbeta both in vitro and in vivo, uncovering a novel mechanism of ERbeta-mediated protection in the vessel wall. In summary, this doctoral work reveals two novel ERbeta-associated proteins that can modulate the response to estrogen both in vitro and in vivo, and may be the target of future therapeutics designed to treat and prevent cardiovascular disease in both men and women.