AGING, ESTROGEN, HSPS AND MYOCARDIAL ISCHEMIA

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DESCRIPTION (Adapted from the Investigator's abstract): The heat shock proteins (HSPs) are an important family of endogenous, protective proteins found in all tissues. In the heart, HSP72, the inducible HSP70, is increased by ischemia and is cardioprotective. Overexpression of other HSPs also protects against cardiac injury. Aging results in a decreased heat shock response in male rats; the effect on females in unknown. Women have less cardiovascular disease than men, but postmenopausal women have an increased incidence of heart disease. Although some of estrogen's protective effects can be explained by changes in lipoprotein profiles, other, unknown factors are involved. Studies in the Principal Investigator's laboratory have shown that estrogen increases levels of HSPs in male rat cardiac myocytes. We hypothesize that, as estrogen increases HSP expression and estrogen protects against CV disease, the decrease in estrogen with aging is associated with a decrease in HSP expression, and contributes to the increased susceptibility of the heart to injury. We propose to study the interaction of estrogen, HSPs and aging in three Specific Aims: 1 Determine the effect of aging versus hormones (17beta-estradiol and progesterone) on heat shock proteins in female rats. These experiments will test 2 hypotheses: 1. Estrogen affects HSP levels in the rat; and 2. Estrogen can increase HSP expression in aging. The expression of HSPs decreases in a number of settings with aging, and these experiments will address the importance of estrogen in this blunting of the heat shock (stress) response. 2. Determine the mechanism of selective induction of HSP72 by estrogen, and whether this is protective. These studies will investigate the mechanisms controlling HSP expression in the cardiac myocyte. E-Determine whether hormone replacement can increase HSP levels in vivo and protect against myocardial ischemia in aging and adult rats. This work will expand on the preliminary findings that estrogen increases HSP levels, and extend them to the in vivo setting of myocardial ischemia. These studies will address the important question of whether the heat shock response is blunted with aging or hormone changes in females, and provide new information about the effects of aging and hormone replacement on the response to ischemia. The long-term goal of this research initiative is to understand gender differences in the HSPs and changes in the HSPs with aging in the heart.