| Pre-menopausal women are known to have a lower incidence of cardiovascular disease (CVD) compared to age matched men. However, after menopause women have an accelerated risk for developing hypertension and atherosclerosis, indicating that the loss of ovarian hormones, particular estrogen, plays a role in the progression of heart disease. Although the actions of E2 have been well characterized, much remains unknown about how E2 protects against the development of CVD and how the loss of estrogens during menopause accelerates this progression.;In this dissertation, we have provided new evidence demonstrating an additional protective effect of 17beta-estradiol, the most active form of estrogen, occurs through the induction of heat shock proteins (HSPs). HSPs protect against ischemic injury and limit cellular injury during cell stress. In this dissertation we demonstrate that the protective role of HSPs against ischemic injury is partially dependant on its nuclear localization upon cell stress. In addition, we present evidence that E2 activates the transcription factor nuclear factor-kappaB (NFkappaB) non-genomically through simulataneous activation of MAP kinase and the PI3-K/Akt pathways, which converge on NFkappaB. Activation of this pathway by E2 leads to HSP induction. We also present a review of the literature on E2 and HSPs in the cardiovascular system, and discuss possible ways in which E2 is able to both activate and inhibit NFkB and modulate its protective and injurious properties.;The second half of the dissertation focuses on changes in the vasculature and in the myocardium with aging and estrogen loss. We have demonstrated that aging with estrogen loss impairs vascular relaxation to endogenous vasoactive substances through the downregulation of the nitric oxide receptor, soluble Guanyl Cyclase (sGC) within the vascular smooth muscle, which can be prevented by immediate E2. In the myocardium, aging leads to an impairment in HSP induction in response to E2, through inhibition of heat shock factor-1, which can not be restored by E2 replacement. However, estrogen replacement in the aged can prevent other detrimental cardiac changes, such as impaired cardiac fractional shortening, increased inflammatory gene expression, oxidative stress and cellular necrosis. |
