SEX HORMONES AND CORONARY ARTERY REACTIVITY

绝经前人群冠状动脉疾病的年龄调整发病率 女性大约比男性落后十年。绝经后， 发病率上升的速度与男性相似。这表明一种 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，我们已经显示出 女性冠脉环对血栓素的收缩作用 比较豚鼠对雄鼠鸟苷环化酶的抑制作用。 此外，相同浓度的cGMP会产生更大的松弛 与男性相比，女性的血栓素收缩的冠状动脉。 这些发现表明，cGMP的合成/分解存在性别二型性。 一氧化氮(NO)是一种具有不同作用的金丝桃体，其作用机制是通过激活 CGMP。一氧化氮刺激血管内皮细胞，但抑制血管平滑肌细胞 扩散。我们已经证明，雌二醇会增加 一氧化氮合酶(NOS)通过增加基因转录。这些 研究结果表明，雌激素可能对冠心病具有双重保护作用 动脉疾病。首先，通过增加内皮细胞衍生的一氧化氮、雌激素 最大限度地减少血栓期间释放的收缩激动剂的反应 队形。第二，抑制血管平滑肌(VSM)细胞 刺激内皮细胞增殖，雌激素减缓 动脉粥样硬化的发展。 因此，我们假设雌激素对卵巢癌有保护作用。 一氧化氮合酶和鸟苷环化酶对冠脉循环的影响 活动。提出用来检验这一假说的实验利用 分离心脏、冠状动脉和培养细胞以研究 生理、生物化学和分子生物学的性别差异。 首先，我们将研究NO/cGMP通路在调控中的作用 细胞内钙离子与雌激素对冠状动脉的反应性 一氧化氮合酶和鸟苷环化酶的生化测定及 特异性抑制剂在冠状动脉离体环中的应用。 第二，我们将确认雌激素和雌激素对nos基因的诱导。 通过Northern/Dot印迹分析确定哪些nos基因被诱导。 第三，我们将通过原位定位nos-mrna的合成部位。 用本实验室研制的豚鼠序列特异性探针进行杂交 实验室。最后，由于弹性蛋白已被证明有助于 我们将研究雌激素对动脉壁增厚的影响。 弹性蛋白基因的诱导以及VSM的细胞生长和增殖。 这项调查将在五年内进行，使用性行为 成熟的(完整的和手术去势的)雄性和雌性豚鼠和 将为雌激素在调节冠状动脉中的作用提供新的证据 动脉反应性通过NO/cGMP途径实现。

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.