17β-Estradiol, Aging, Inflammation, and the Stress Response in the Female Heart

Heat shock proteins (HSPs) are a cardioprotective class of proteins induced by stress and regulated by the transcription factor, heat shock factor (HSF)-1. 17 beta-estradiol (E-2) indirectly regulates HSP expression through rapid activation of nuclear factor-kappa B (NF-kappa B) and HSF-1 and protects against hypoxia. As males experience a loss of protective cellular responses in aging, we hypothesized that aged menopausal (old ovariectomized) rats would have an impaired HSP response, which could be prevented by immediate in vivo E-2 replacement. After measuring cardiac function in vivo, cardiac myocytes were isolated from ovariectomized adult and old rats with and without 9 weeks of E-2 replacement. Myocytes were treated with E-2 in vitro and analyzed for activation of NF-kappa B, HSF-1, and HSP expression. In addition, we measured inflammatory cytokine expression and susceptibility to hypoxia/reoxygenation injury. Cardiac contractility was reduced in old ovariectomized rats and could prevented by immediate E-2 replacement in vivo. Subsequent investigations in isolated cardiac myocytes found that in vitro E-2 activated NF-kappa B, HSF-1, and increased HSP 72 expression in adult but not old rats. In response to hypoxia/reoxygenation, myocytes from adult, but not old, rats had increased HSP 72 expression. In addition, expression of the inflammatory cytokines TNF-alpha and IL-1 beta, as well as oxidative stress, were increased in myocytes from old ovariectomized rats; only the change in cytokine expression could be attenuated by in vivo E-2 replacement. This study demonstrates that while aging in female rats led to a loss of the cardioprotective HSP response, E-2 retains its protective cellular properties. (Endocrinology 152: 1589-1598, 2011)