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Hormone replacement therapy, smoking & lipoprotein oxidation

Institution: La Jolla Institute for Molecular Medicine
Investigator(s): Carole Banka, Ph.D.
Award Cycle: 1998 (Cycle 7) Grant #: 7RT-0101A Award: $245,584
Subject Area: Cardiovascular Disease
Award Type: Research Project Awards

Initial Award Abstract
When women reach menopause, their risk for heart disease increases, in part, because of the aging process and, in part, because their ovaries no longer make estrogen and progesterone. Estrogen is known to reduce cardiovascular risk significantly. Cigarette smoking constitutes a third significant risk factor in postmenopausal women and environmental tobacco smoke (ETS) also contributes to cardiovascular risk in "passive" smokers. Therefore, it appears that the lack of ovarian hormones associated with menopause and exposure to cigarette smoke (passive or active) constitute the two most important risk factors for heart disease in otherwise healthy women. Hormone replacement therapy (HRT), the replacement of estrogen (or estrogen and progesterone) through medication, reduces the risk of heart disease by as much as 50% in postmenopausal women. Yet physicians are hesitant to prescribe HRT for women smokers, due to the historical (albeit rare) occurrence of blood clotting (and the resulting risk of blood vessel occlusion and/or stroke) in women who smoke and take contraceptive pills that contain estrogen. However, the risk of clotting associated with HRT is minimal and increases only slightly in HRT-treated women who smoke. Although the ideal approach to management of heart disease risk in postmenopausal women would include smoking cessation, for those women who chose to continue smoking, or who live in a situation associated with exposure to environmental tobacco smoke, HRT may be an especially important intervention. It is my goal to develop a small animal model for the first rigorous studies of the interactions between environmental tobacco smoke, postmenopausal status and hormone replacement therapy as they relate to heart disease. To this end, I have designed this proposal to accomplish the following specific aims:

Aim #1: To test the hypothesis that exposure to environmental tobacco smoke (ETS) will accelerate artery disease in normal mice and to a greater extent, in mice whose ovaries have been removed (postmenopausal mice).

Aim #2: To test the hypothesis that estrogen, and estrogen + progesterone, will partially reverse the acceleration in artery plaque formation resulting from removal of the ovaries and from ETS exposure.

Aim #3: To test the hypothesis that factors involved in ETS-induced acceleration of artery disease include oxidant stress in addition to increases in cholesterol levels, and that cholesterol levels and oxidant stress are reduced as a result of HRT.

The successful completion of these aims will yield valuable information concerning 1) the extent and mechanisms of ETS-mediated acceleration of arterial disease; 2) the additive effects of ETS and postmenopausal status on risk of heart disease; 3) the mechanisms underlying protective effects of estrogens; and 4) the interactions of ETS and hormone replacement therapy.

Final Report
Epidemiologic evidence suggests that postmenopausal women who smoke are protected from heart disease by hormone replacement therapy to a greater extent than nonsmokers who use hormone replacement therapy. To determine if this relationship holds true for women exposed to environmental tobacco smoke (ETS) and to define the interactions between ETS exposure and estrogen treatment, we chose to use mice susceptible to atherosclerosis as an experimental model. We had previously shown that removing the ovaries from young ("pubertal") female low density lipoprotein receptor-deficient (LDLR-/-) mice resulted in a doubling of aortic atherosclerosc lesion and that estrogen replacement in the form of implantable slow-release estrogen pellets reversed the increase in vascular lesions resulting from ovariectomy. For the current study, aimed at examining postmenopausal conditions, mature female LDLR-/- mice were castrated, fed a high-fat, high-cholesterol diet (HUD) for 12 weeks and exposed to filtered air (FA) or to aged and diluted sidestream cigarette smoke (ADSS) as a surrogate for ETS for 10 of the 12 weeks. Sham operated females exposed to FA or ADSS served as controls. At termination of the study, aortae were collected for lesion analysis; uteri were collected for weight determination (a measure of the effectiveness of ovariectomy and estrogen status); and plasma samples were collected for lipid analyses.

In mice subjected to low-dose ADSS (1 mg/m3 total suspended particulates), there was an increase in aortic lesion area compared with FA controls only in the ovariectomized (OVX) females; however, a statistically significant increase in atherosclerosis was seen in both OVX and intact females exposed to high-dose ADSS (5 Mg/M3 total suspended particulates). None of the increases in lesion area correlated with lipid parameters suggesting that the influence of ADSS on atherosclerosis could not be explained by differences in plasma cholesterol levels. In conclusion, in mature female LDLR-/- mice, we found a dose-dependent, ADSS-mediated increase in atherosclerosis that was exacerbated by the absence of circulating ovarian steroids. These results support our hypothesis that estrogen replacement will confer protection from cardiovascular disease in women exposed to "second hand" smoke.