KLF14 and Cardiovascular Disease

腹主动脉瘤(Aaa)是一种无症状的疾病，如果破裂，死亡率很高(65%~85%)。 发生。手术修复是唯一有效的治疗方法，但仅限于符合条件的患者(约占总数的10%)。不是 已发现有效的药理学方法来限制AAA的进展和破裂。男性性行为是一种 AAA的重要危险因素，男女患病率比约为4-6：1。发生这种性行为的原因 差异尚不清楚，但女性AAA的延迟发病表明雌激素及其受体(ER) 可能在降低AAA患病率方面发挥作用。雌激素对腹主动脉瘤的保护作用 通过减少促炎介质和蛋白分解途径建立动物模型。然而，龙- 长期雌激素治疗由于不良副作用，不能广泛应用于AAA患者的治疗。人类 遗传学研究发现Kruppel-like factor14(KLF14)与慢性代谢密切相关 有性别差异的疾病。我们先前报道了KLF14及其激活剂的生物学功能， 培己胺，临床上用于治疗心绞痛和心力衰竭，在脂代谢方面表现出较强的 KLF14的抗炎作用。我们在这里描述的初步数据确定了巨噬细胞- 选择性KLF14基因敲除小鼠显示雌性AAA发病率显著增加，与 提示雌激素/ERα/β途径的保护作用受损。除了抑制之外 KLF14对炎症反应和基质金属蛋白酶-9活性的影响，进一步发现雌激素上调 KLF14的表达，而KLF14又是一个关键的转录因子，上调了 巨噬细胞中的ERα/β，揭示了一个前馈环路，这可能有助于观察到的性别差异。 培氟西林以KLF14依赖的方式增加ERα/β水平。一种胆固醇代谢产物，24- 羟基胆固醇(24HC)作为内源性ER-α/β激动型分子发挥作用，增强内源性ER-TdR活性。 培己胺对巨噬细胞的炎症作用。最重要的是，培己胺的使用显著 减少AAA的分离/破裂，提高雄性小鼠的存活率。根据我们的初步发现， 拟议的项目将检验KLF14预防AAA发展/夹层的中心假设 通过抑制炎症和增强巨噬细胞中ER-α/β依赖的保护作用来抑制/破裂。这个 特定的目的将1)确定巨噬细胞KLF14是AAA小鼠性别差异的重要调节因素 模型；2)确定KLF14如何调节导致性二型性的雌激素/雌激素受体途径 对AAA的保护作用；以及3)确定KLF14的激活抑制了脑发育/夹层/破裂。 AAA小鼠模型。基于KLF14在AAA中的性别特异性功能，这一机制研究将 将KLF14作为新的治疗靶点，将为临床应用奠定坚实的基础 KLF14激活剂，如培己胺，作为治疗AAA的可行药物，具有改变电流的潜力 腹主动脉瘤的治疗范例。

Abdominal aortic aneurysm (AAA) is an asymptomatic disease of high mortality rate (65% to 85%) if rupture occurs. Surgical repair is the only effective treatment, but limited to eligible patients (about 10% of total). No effective pharmacological approach has been identified to limit AAA progression and rupture. Male sex is an important risk factor for AAA, with about 4-6:1 male to female prevalence ratio. The reasons for this sex disparity are unknown, but the delayed onset of AAA in women suggests that estrogen and its receptors (ERs) may play a role in reducing the prevalence of AAA. Administration of estrogen has protective effects in AAA animal models through reduction of pro-inflammatory mediators and the proteolytic pathway. However, long- term estrogen therapy cannot be widely applied to treat AAA patients due to undesirable side-effects. Human genetic studies uncovered that Kruppel-like factor 14 (KLF14) is robustly associated with chronic metabolic diseases with a sex difference. We previously reported the biological function of KLF14 and its activator, perhexiline, clinically used to treat angina and heart failure, in lipid metabolism and demonstrate the strong anti-inflammatory effect of KLF14. Our preliminary data described herein established that macrophage- selective Klf14 knockout mice showed significantly increased AAA incidence rates in females, comparable to those in males, suggesting impaired protective effects of estrogen/ERα/β pathway. Besides the inhibitory effects of KLF14 on the inflammatory response and MMP-9 activity, we further found that estrogen upregulates the expression of KLF14 while KLF14, in turn, is a critical transcription factor upregulating the expression of ERα/β in macrophages, uncovering a feedforward loop that may contribute to the observed sex disparity. Perhexiline increased the levels of ERα/β in a KLF14-dependent manner. A cholesterol metabolite, 24- hydroxycholesterol (24HC), functioned as an endogenous ERα/β agonistic molecule and enhanced the anti- inflammatory effect of perhexiline in macrophages. Most importantly, administration of perhexiline significantly reduced AAA dissection/rupture and increased survival rate in male mice. Based on our preliminary findings, the proposed project will test the central hypothesis that KLF14 protects against AAA development/dissection /rupture by suppressing inflammation and enhancing ERα/β-dependent protective roles in macrophages. The specific aims will 1) define that macrophage KLF14 is an important regulator of sex differences in AAA mouse models; 2) determine how KLF14 regulates the estrogen/ERs pathway which contributes to sex-dimorphic protective effects on AAA; and 3) determine that activation of KLF14 inhibits development/dissection/rupture in AAA mouse models. Based on the sex-specific functions of KLF14 in AAA, this mechanistic research will establish KLF14 as a novel therapeutic target and will set a solid foundation towards clinical utilization of KLF14 activators, like perhexiline, as a viable drug therapy for AAA, with the potential to change current treatment paradigms for AAA.