Effects of Statins on Endometrial Stoma

子宫内膜异位症是影响育龄妇女最常见的良性妇科疾病之一。子宫内膜异位种植体的形成需要子宫内膜间质和腺体的异位附着和增殖。子宫内膜异位症的突出特征包括炎症反应和氧化应激增加。 我们提出了一个新的假说，即他汀类药物抑制甲羟戊酸途径将抑制子宫内膜基质和子宫内膜异位症植入物的生长，以及减少氧化应激。 具体而言，我们假设他汀类药物通过以下方式影响子宫内膜间质细胞：（i）抑制蛋白质的异戊二烯化，特别是小GTP酶，如Ras和Rho，从而调节调节生长的信号转导途径，以及（ii）减少也影响生长的活性氧物质的产生。这一基本假设基于以下证据：在几种组织中，如血管平滑肌，甲羟戊酸途径的产物促进小GTP酶的异戊二烯化，从而激活促进生长的信号转导途径。在血管平滑肌和其他几种组织中，他汀类药物抑制甲羟戊酸途径可抑制生长并发挥抗氧化作用。 我们的初步研究表明，适度的氧化应激刺激子宫内膜间质增生。此外，我们的初步数据表明，他汀类药物抑制子宫内膜间质增殖，同时阻断ERK 1/2磷酸化。该提案的具体目的是深入研究他汀类药物对生长和氧化应激的影响：（i）在子宫内膜基质细胞中，（ii）在子宫内膜异位症植入物中， 裸鼠模型。这些研究将为子宫内膜组织生长和功能的调控机制提供新的见解。最终，拟议的研究可能会导致子宫内膜异位症新疗法的发展，例如他汀类药物的临床应用。

Endometriosis is one of the most common benign gynecologic conditions affecting women of reproductive age. Formation of endometriotic implants requires ectopic attachment and proliferation of endometrial stroma and glands. Prominent features of endometriosis include inflammatory reaction and increased oxidative stress. We propose a novel hypothesis that inhibition of the mevalonate pathway by statins will inhibit growth of endometrial stroma and endometriotic implants as well as decrease oxidative stress. Specifically, we postulate that statins affect endometrial stromal cells by: (i) inhibiting isoprenylation of proteins, especially small GTPases such as Ras and Rho leading to modulation of signal transduction pathways regulating growth, and (ii) decreasing generation of reactive oxigen species, which also affect growth. This underlying hypothesis is based on evidence that in several tissues, such as vascular smooth muscle, products of the mevalonate pathway facilitate isoprenylation of small GPTases and thus activate signal transduction pathways promoting growth. In vascular smooth muscle and in several other tissues, inhibition of the mevalonate pathway by statins inhibits growth and exerts antioxidant effects. Our preliminary studies have shown that moderate oxidative stress stimulates endometrial stromal proliferation. Furthermore, our preliminary data indicate that statins inhibit endometrial stromal proliferation, while blocking ERK1/2 phosphorylation. The specific aims of this proposal are to study in depth the effects of statins on growth and oxidative stress: (i) in endometrial stromal cells and (ii) in endometriotic implants in a nude mouse model. These studies will provide new insight into the mechanisms regulating growth and function of endometrial tissues. Ultimately, the proposed research may lead to the development of new treatements of endometriosis, such as clinical use of statins.