SEX HORMONES AND CORONARY ARTERY REACTIVITY

绝经前妇女冠心病的年龄校正发病率 妇女比男子大约落后10年。 绝经后， 发病率上升的速度与男子相似。 这表明 激素，可能是雌激素，通过以下方式保护冠状动脉和心脏： 未知的机制 在初步研究中，我们发现 女性冠状动脉环对血栓素的收缩 与鸟苷酸环化酶抑制后的雄性豚鼠相比。 此外，相同浓度的cGMP产生更大的松弛。 与男性相比，女性的血栓素收缩冠状动脉。 这些发现表明cGMP合成/分解中的性二态性。 一氧化氮（NO）是一种具有多种作用的自泌素， cGMP。 NO刺激内皮细胞但抑制平滑肌细胞 增殖 我们已经证明，雌二醇增加的活动， 一氧化氮合酶（NOS）通过增加基因转录。 这些 研究结果表明，雌激素可能提供双重保护， 动脉疾病 首先，通过增加内皮源性NO，雌激素 最小化对血栓形成过程中释放的收缩激动剂的反应， 阵 第二，通过抑制血管平滑肌（VSM）细胞 和刺激内皮细胞增殖，雌激素减缓了 动脉粥样硬化的发展。 因此，我们假设雌激素对乳腺癌的发生具有保护作用。 通过NOS和鸟苷酸环化酶的增加来增加冠状动脉循环 活动 为检验这一假设而提出的实验利用了 分离的心脏，冠状动脉，和培养的细胞来研究 生理学、生物化学和分子生物学的性别差异。 首先，我们将研究NO/cGMP途径在调节细胞凋亡中的作用。 细胞内钙离子和冠状动脉反应性雌激素使用两者 一氧化氮合酶和鸟苷酸环化酶的生化测定， 特异性抑制剂对离体冠状动脉环的应用。 其次，我们将证实雌二醇对nos基因的诱导作用， 使用北方/斑点印迹分析确定哪些nos基因被诱导。 第三，我们将通过原位杂交定位nos-mRNA的合成位点， 杂交使用豚鼠序列特异性探针在我们开发的 实验室 最后，由于弹性蛋白已被证明有助于 动脉壁增厚，我们将研究雌激素对 弹性蛋白基因的诱导以及VSM细胞的生长和增殖。 调查将在五年内进行， 成熟（完整和手术去势）雄性和雌性豚鼠， 将为雌激素在调节冠状动脉粥样硬化中的作用提供新的证据。 通过NO/cGMP途径的动脉反应性。

The age adjusted incidence of coronary artery disease of premenopausal women lags approximately ten years behind that of men. After menopause, the incidence rises at a rate similar to that of men. This suggests a hormone, possibly estrogen protects the coronary arteries and heart by unknown mechanisms. In preliminary study, we have shown diminished contraction to thromboxane of coronary artery rings prepared from female guinea pigs compared to males after the inhibition of guanylate cyclase. Further, equal concentrations of cGMP produce greater relaxation of thromboxane-contracted coronary arteries from females compared to males. These findings suggest a sexual dimorphism in cGMP synthesis/breakdown. Nitric oxide (NO), an autacoid with diverse roles works by activating cGMP. NO stimulates endothelial but inhibits smooth muscle cell proliferation. We have shown that estradiol increases the activity of nitric oxide synthase (NOS) through increased gene transcription. These findings suggest estrogen may provide dual protection against coronary artery disease. First, by increasing endothelium-derived NO, estrogen minimizes the response to contractile agonists released during thrombus formation. And second, by inhibiting vascular smooth muscle (VSM) cell and stimulating endothelial cell proliferation, estrogen slows the development of atherosclerosis. Thus, we hypothesize that estrogen exerts a protective effect on the coronary circulation via its augmentation of NOS and guanylate cyclase activities. The experiments proposed to test this hypothesis utilize isolated hearts, coronary arteries, and cultured cells to study the physiology, biochemistry and molecular biology of gender differences. First, we will examine the role of the NO/cGMP pathway in regulating intracellular Ca2+ and coronary artery reactivity by estrogen using both biochemical measurements of NOS and guanylate cyclase and by the application of specific inhibitors to isolated coronary artery rings. Second, we will confirm the induction of the nos-genes by estradiol and determine which nos-genes are induced using Northern/Dot blot analyses. Third, we will localize the site of nos-mRNA synthesis by in situ hybridization using guinea pig sequence specific probes developed in our laboratory. Finally, since elastin has been shown to contribute to arterial wall thickening, we will investigate the effect of estrogen on elastin gene induction as well as cell growth and proliferation of VSM. The investigation will be carried out over five years using sexually mature (intact and surgically castrated) male and female guinea pigs and will provide new evidence for the role of estrogen in modulating coronary artery reactivity via the NO/cGMP pathway.