15-PGDH as a better therapeutic target than aspirin in decreasing risk of intracranial aneurysm rupture in men and women equally

项目摘要/摘要 未破裂的小型颅内动脉瘤(UIA)(直径3-7毫米)平均每年有 每年增长(≥1 mm)3%(2-4年随访范围：7%-21%)1-11个颅内动脉瘤(IA) 与不扩大的相比，扩大的破裂风险增加12-24倍。1-11这些数据显示 AHA/ASA在其2015年指南中强烈建议对符合以下条件的UIA进行手术或血管内治疗 扩大，12但需要这些昂贵的侵入性程序，这些程序具有相关的发病率和 如果能够开发药物治疗来防止IA的生长或破裂，死亡率可能是有限的。 基于对人类和动物进行的一系列关于UIAs的研究数据，阿司匹林已经显示出 安全、廉价、有效的治疗方法可减少IA的生长和破裂。 但是，女性和男性对ASA的反应是平等的吗？答案是否定的。(一)我们的动物研究显示 在对ASA的生物反应和ASA降低IA风险的能力方面，存在性别差异 小鼠体内破裂。15(B)我们发现对15-PGDH表达的影响是这一现象的一个潜在原因 并通过激活雌性小鼠的这种酶和抑制雄性小鼠的这种酶来逆转这些效应。 使用ISUIA队列数据证实在人类中发现了小鼠对ASA的性别特异性反应， ASA在减少男性IA破裂方面比女性有效20%。15(D)血液分析 从人的IA囊内收集的结果显示，与男性相比，男性的15-PGDH水平显著升高 雌性，证实了我们在小鼠身上的发现，并增加了更多对ASA和15- 作为对这种反应的潜在解释。23 我们的建议试图验证这些基本假设：(1)15-PGDH的激活降低了IA的风险 通过：a)减少PGE2的有害表达和b)将PGE2转化为15-酮PGE2，从而起作用 作为PPAR的内源性激动剂，已知可降低IA破裂的风险；(2)15- Keto PGE2是细胞特异性的平滑肌细胞和巨噬细胞。 为了检验这些假设，我们将实现以下两个具体目标： 具体目标1：验证激活15-PGDH同样降低男性UIA破裂风险的假设 和雌性WT小鼠通过(A)减少PGE2的表达和(B)增加15-keto PGE2作为一种 我们发现的内源性PPAR激动剂降低了IA破裂的风险。具体目标2：测试 假设15-酮前列腺素E_2(15-酮-前列腺素E_2的最终副产物)的作用 内源性PPAR激活剂)主要作用于平滑肌细胞和巨噬细胞(MΦ)。

PROJECT SUMMARY / ABSTRACT Small unruptured intracranial aneurysms (UIAs) (3–7 mm in diameter) have an average annual likelihood of growth (≥1 mm) of 3% per year (range: 7–21% over 2–4 years of follow-up).1-11 Intracranial aneurysms (IA) that enlarge have 12–24 times increased risk of rupture compared to those that do not.1-11 These data compelled the AHA/ASA in their 2015 guidelines to strongly recommend surgical or endovascular treatment of UIAs that enlarge,12 but the need for these expensive invasive procedures, which have associated morbidity and mortality, could be limited if pharmaceutical treatments could be developed to prevent IA growth or rupture. Based on data from a series of studies in humans and animals regarding UIAs, Aspirin has shown to safe, inexpensive, and effective treatment to decrease IA growth and rupture. But do women and men respond equally to ASA? The answer is NO. (A) Our animal study revealed that there are sex-specific differences in the biologic response to ASA and the ability of ASA to reduce the risk of IA rupture in mice.15 (B) We identified effects on expression of 15-PGDH as a potential cause of this phenomenon and reversed these effects by activating this enzyme in female mice and inhibiting it in male mice.15 (C) The finding of sex-specific responses to ASA in mice was confirmed in humans using data from ISUIA cohort, with ASA being 20% more effective in reducing IA rupture in males than females.15 (D) Serum analysis of blood collected from within human IA sacs showed significant elevation of 15-PGDH in males when compared to females, confirming our findings in mice and adding more evidence of sex differential response to ASA and 15- PGDH as potential explanation for this response.23 Our proposal seeks to test these primary hypotheses: (1) activation of 15-PGDH decreases the risk of IA rupture by: a) decreasing the harmful expression of PGE2 and b) converting PGE2 to 15-keto PGE2 which acts as an endogenous agonist of PPAR, which is known to decrease the risk of IA rupture; (2) the effect of 15- keto PGE2 is cell-specific to smooth muscle cells and macrophages. To test these hypotheses, we will perform these two specific aims: Specific Aim 1: Test the hypothesis that activation of 15-PGDH decreases risk of UIA rupture equally in male and female WT mice by (A) decreasing expression of PGE2 and (B) increasing 15-keto PGE2 which acts as an endogenous agonist of PPAR which we showed decreases the risk of IA rupture. Specific Aim 2: Test the hypothesis that the effect of 15-keto PGE2 (final byproduct of 15-PGDH which functionally acts as an endogenous PPAR activator) primarily acts in smooth muscle cells (SMC) and macrophages (MΦ).