Effect of estrogen on ETS-induced glyco-oxidation
Abstracts
Initial Award Abstract |
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Both diabetes and environmental tobacco smoke (ETS) are very strongly associated with arterial disease but very little is known about how these factors contribute to increased disease development. A common link between these two diverse risk factors is that each increase a modification of the arterial wall that is clearly associated with arterial disease. This modification occurs through a process termed glyco-oxidation. Glyco-oxidation increases accumulation of low-density lipoprotein (LDL) in the artery wall and is positively correlated with arterial disease in many diverse populations. While estrogen is widely believed to protect against arterial disease, its mechanism of action is also poorly defined.
The goal of this proposal is to examine the effect of estrogen on LDL accumulation in diabetic and ETS exposed animals and to examine the effect of estrogen on glyco-oxidation of collagen (a major component of the artery wall) in vitro. We hypothesize that estrogen will decrease LDL accumulation in diabetic animals but be less effective for ETS exposed animals. To test this hypothesis, we will examine the ability of estrogen to decrease glyco-oxidative modification of collagen in vitro. Such in vitro studies can provide information concerning how estrogen may act to decrease arterial modifications that can contribute to arterial disease. We will also examine the effect of estrogen on LDL accumulation caused by ETS exposure and/or diabetes in vivo.
Information obtained from this study could potentially have a major positive impact on the understanding of how cardiovascular disease develops as a consequence of ETS exposure and diabetes. Additionally, insight into the role of estrogen in preventing arterial disease can be obtained. |
Final Report |
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Both diabetes and environmental tobacco smoke (ETS) are very strongly associated with arterial disease but very little is known about how these factors contribute to increased disease development. A common link between these two diverse risk factors is that each increase a modification of the arterial wall that is clearly associated with arterial disease. This modification occurs through a process termed glyco-oxidation. Glyco-oxidation increases accumulation of low-density lipoprotein (LDL) in the artery wall and is positively correlated with arterial disease in many diverse populations. While estrogen is widely believed to protect against arterial disease, mechanisms of action are poorly defined. The goal of this proposal was to evaluate the antioxidant properties of estrogen and its atheroprotective potential following ETS exposure and/or glycemic stress. To accomplish these objectives we pursued two specific aims: 1) Investigate the actions of diabetes, ETS and estrogens on vascular LDL accumulation in BALB/c mice. 2) Examine the ability of estradiol to attenuate glyco-oxidative damage to collagen in vitro as a result of glycemic stress and/or ETS exposure and to elucidate the specific reaction pathways affected by estradiol.
Our first specific aim involved LDL flux measurement in control, diabetic and ETS-treated mice with and without circulating estrogen. We have completed all LDL flux measurements for non-ETS-exposed animals. Diabetes significantly increased LDL accumulation over control. The presence of estradiol had no effect on diabetes-induced LDL accumulation. Our second aim involved determining the ability of estrogen to decrease ETS and/or glycemic stress-induced glyco-oxidative damage to collagen in vitro. Pathways involved in the formation of glyco-oxidation products include classic Maillard reactions, glucose auto-oxidation, lipid oxidation, and ETS exposure. Estrogen was found to decrease lipid and glucose oxidation as well as the formation of carbohydrate-derived glyco-oxidation products (via Maillard reactions) but was not able to decrease ETS-derived glyco-oxidation. In light of estrogen's inability to decrease ETS-induced glyco-oxidation, we examined the effects of a very potent glyco-oxidation inhibitor (aminoguanidine) on ETS-induced LDL oxidation. ETS-exposed LDL was significantly more oxidized than non-exposed LDL. Pre-incubation of LDL with 0.1 mg/ml aminoguanidine had no effect but 10 mg/ml significantly decreased ETS-induced LDL oxidation. These results suggest that only high doses of aminoguanidine inhibited LDL oxidation due to ETS-exposure.
These data clearly demonstrate that ETS poses a severe glyco-oxidative stress to the vascular system that is only minimally affected by known inhibitors of glyco-oxidation. Further, we have shown that estrogen is capable of inhibiting many pathways contributing to glyco-oxidative damage but is ineffective at inhibiting ETS-induced glyco-oxidation. These in vitro findings corroborate previous in vivo experiments showing that the protective effect of estrogen on arterial permeability is eliminated in ETS-exposed animals. Our data may help to explain the particularly toxic effect ETS exposure has on the cardiovascular system and could potentially have a major positive impact on the understanding of the role of estrogen in ETS and diabetes-induced vascular disease. |
